Pcsk9 antibody preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device

ABSTRACT

Embodiments provide swallowable devices, preparations and methods for delivering therapeutic agents (TAs) within the GI tract such as antibodies (AP-antibodies) or other proteins which neutralize PCSK9 molecules. Many embodiments provide a swallowable device e.g., a capsule for delivering TAs into the intestinal wall (IW). Embodiments also provide TA preparations that are configured to be contained within the capsule, advanced from the capsule into the IW and/or peritoneum and degrade to release the TA into the bloodstream to produce a therapeutic effect. The preparation can be operably coupled to delivery means having a first configuration where the preparation is contained in the capsule and a second configuration where the preparation is advanced out of the capsule into the IW. Embodiments are particularly useful for delivery of AP-antibodies and related TA&#39;s for the treatment of cholesterol, lipid and related conditions where such TAs are poorly absorbed and/or degraded within the GI tract.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalApplication No. 62/215,586, (Attorney Docket No. 42197-736.101), filedSep. 8, 2015, the entire content of which is incorporated herein byreference for all purposes. This application is also a continuation-inpart of U.S. patent application Ser. No. 15/150,379, (Attorney DocketNo. 42197-734.201), filed May 9, 2016, which is incorporated byreference herein for all purposes.

This application incorporates by reference the following U.S Patent andprovisional patent applications for all purposes. Provisional U.S.Patent Application Ser. No. 61/571,642, entitled “Therapeutic AgentPreparation for Delivery Into a Lumen of The Intestinal Tract Using aSwallowable Drug Delivery Device”, filed on Jun. 29, 2011; and U.S.Provisional Application No. 61/571,641, entitled “Device, System andMethod for the Oral of Therapeutic Compounds”, filed Jun. 29, 2011, bothof which are fully incorporated by reference herein for all purposes;and this application is also a continuation in part of the followingU.S. patent application Ser. No. 12/978,233, entitled “Swallowable DrugDelivery Device and Methods of Drug Delivery”, filed on Dec. 23, 2010;U.S. patent application Ser. No. 12/978,164, entitled “Therapeutic AgentPreparation for Delivery Into a Lumen of The Intestinal Tract Using aSwallowable Drug Delivery Device”, filed on Dec. 23, 2010; U.S. patentapplication Ser. No. 12/978,301, entitled “Swallowable Drug DeliveryDevice and Methods of Drug Delivery”, filed on Dec. 23, 2010. U.S.patent application Ser. No. 13/532,589, entitled “Device, System AndMethods For The Oral Delivery Of Therapeutic Compounds” filed on Jun.25, 2012; U.S. Pat. No. 8,809,269, entitled “Therapeutic AgentPreparations for Delivery into A Lumen of the Intestinal Tract using aSwallowable Drug Delivery Devices”; U.S. Provisional Patent ApplicationSer. No. 61/993,907, entitled, “Pharmaceutical Compositions And MethodsFor Fabrication Of Solid Masses Comprising Polypeptides And/Or Proteins”filed on May 15, 2014; U.S. Provisional Patent Application Ser. No.62/156,105, entitled, “Pharmaceutical Compounds And Methods ForFabrication Of Solid Masses Comprising Polypeptides And/Or Proteins,Filed May 1, 2015; and U.S. Provisional Patent Application Ser. No.62/159,134 entitled “Anti-Interleukin Antibody Preparations For DeliveryInto A Lumen Of The Intestinal Tract Using A Swallowable Drug DeliveryDevice” filed May 8, 2015.

BACKGROUND OF THE INVENTION Field of the Invention

Embodiments of the invention relate to orally deliverable drug and othertherapeutic agent formulations and swallowable drug delivery devices fordelivery those formulations to the small intestine. More specifically,embodiments of the invention relate to orally deliverable drugformulations such as antibodies to PCSK9. Still more specifically,embodiments of the invention relate to orally deliverable solid drugformulations such as antibodies to PCSK9.

While there has been an increasing development of new drugs in recentyears for the treatment of a variety of diseases, many have limitedapplication because they cannot be given orally. This is due to a numberof reasons including: poor oral toleration with complications includinggastric irritation and bleeding; breakdown/degradation of the drugcompounds in the stomach; and poor, slow or erratic absorption of thedrug. Conventional alternative drug delivery methods such as intravenousand intramuscular delivery have a number of drawbacks including pain andrisk of infection from a needle stick, requirements for the use ofsterile technique and the requirement and associated risks ofmaintaining an IV line in a patient for an extended period of time.While other drug delivery approaches have been employed such asimplantable drug delivery pumps, these approaches require thesemi-permanent implantation of a device and can still have many of thelimitations of IV delivery. Thus, there is a need for an improved methodfor delivery of drugs and other therapeutic agents, including a need forimproved delivery of antibodies for treatment of cardiovascular andother conditions.

Elevated plasma levels of LDL (low density lipoprotein, cholesterolincluding LDL-C) a condition known as hypercholesterolemia) has beenshown to be a key risk factor for the development of atherosclerosis andassociated ischemic cardiovascular disease (CVD), such as myocardialinfarction and stroke which are the leading cause of death in the US.High plasma levels of LDL-C levels are highly inheritable and a numberof molecular defects have been shown to cause such high levels. One ofthe pivotal factors in LDL metabolism is the LDL receptor (LDLR). Thisis due to its capacity to bind and subsequently clear LDL derivedcholesterol derived from the circulation. LDL bound to the LDLR isinternalized into clathrin-coated pits and subsequently undergoeslysosomal degradation. The LDLR is then recycled back to the plasmamembrane where it can bind more LDL. Internalization and re-shuttling ofthe receptor towards the plasma membrane is a continuous process. Themolecule Proprotein convertase subtilisin kexin type 9 (PCSK9) plays apivotal role in this process since it promotes the degradation of theLDLR and prevents it from recycling to the membrane. PCSK9 specificallyacts by reducing the amount of LDLR at the cell surface of hepatocytes.This was first demonstrated in mouse models and inferred by humangenetic studies. Numerous overexpression and knockdown/knockout animalstudies clearly show that PCSK9 targets the LDLR for degradation. Inparticular, a series of parabiosis experiments showing that PCSK9 issecreted from liver cells, circulates in the plasma, binds to LDLR, andis subsequently internalized together with the LDLR, thereby promotingthe cellular degradation of the receptor.

While antibodies to PCSK9 have been developed as a possible treatmentfor hypercholesterolemia, the antibodies must be delivered by subdermalinjections in biweekly doses or even longer intervals. There a number ofdrawbacks to this approach. These include giving the patient extremelyhigh doses of the antibodies exposing them to the possibility of one ormore allergic reactions (e.g., anaphylactic shock, edema, difficultybreathing, fever, etc.) or other adverse event as well as thedevelopment of an immunogenic reaction to the antibodies (e.g. thedevelopment by the patient of antibodies to the PCSK9 antibodies, aswell as erythema and other adverse reaction the injection cite). Theyalso require the patient to come into the hospital every week to twoweeks for the shot. Oral delivery does not have many of thesecomplications as the doses can be delivered in much smaller amountswhich do not cause these adverse events. However, currently antibodiessuch as PCSK9 antibodies cannot be delivered orally as the acids andenzymes in the intestinal tract such a various proteases would breakdown the antibodies before they are able to be absorbed into the smallintestine. What is needed therefore, are compositions and methods fordelivering these antibodies orally and in smaller more frequent doses(e.g. daily) but to do so in a manner which does not cause degradationof the antibodies before they are taken up into the wall of the smallintestine.

BRIEF SUMMARY OF THE INVENTION

Embodiments of the invention provide devices, systems, kits and methodsfor delivering drugs and other therapeutic agents to various locationsin the body. Many embodiments provide a swallowable device fordelivering drugs and other therapeutic agents within theGastrointestinal (GI) tract. Particular embodiments of the inventionprovide a swallowable device such as a capsule for delivering drugs andother therapeutic agents into the wall of the small intestine and/orsurrounding tissue (e.g. the peritoneum) or other GI organ wall.Embodiments of the invention are particularly useful for the oraldelivery of therapeutic agents such as various PCSK9 neutralizingproteins (PN-protein), particularly antibodies which are poorlyabsorbed, poorly tolerated and/or degraded within the GI tract. Further,embodiments of the invention can be used to orally deliver such PNproteins including PCSK9 neutralizing antibodies (PN-antibodies, alsoreferred to herein as AP-antibodies) which were previously only capableof being delivered by injection including various non-vascular injectedforms of administration such as intramuscular or subcutaneous injection.Moreover, such embodiments can be used to provide an orally deliveredtreatment for hypercholesterolemia or other cholesterol related diseaseor condition using PN antibodies (or other PN-proteins) without the sideeffects associated with subcutaneous injection or other form of injecteddelivery of these compounds.

In one aspect of the invention, the invention provides a therapeuticagent preparation for delivery into the wall of the small intestineand/or surrounding tissue (e.g. the peritoneum) or other location in theintestinal tract, comprising a therapeutically effective dose of atleast one PCSK9 neutralizing protein (PN protein or PNP also known as aPCSK9 binding protein or PB-protein) such as an antibody which binds toPCSK9 molecules (herein anti-PCSK9 antibodies or AP-antibodies) or itsreceptors along with their respective analogues and derivatives. TheAP-antibodies used in one or more embodiments of the therapeuticpreparations can be full-length antibodies or an antigen-binding portionthereof. The preparation may have a shape and material consistency to becontained in an embodiment of the swallowable capsule (or like device)and delivered from the capsule into the intestinal wall to release thedose of AP-antibody or other PN-protein from within the intestinal wall.Such shapes may correspond to various structures having a pointed endsuch as various dart-like, or needle like shapes or structures. Thepreparation may be in solid, liquid, or powder form. Preferably, thepreparation including the AP-antibody or other PN protein is in solidform allowing the preparation to be stored for extended periods of time,as well as to be shaped (e.g. into a tissue penetrating shape) and havea mechanical force or other force exerted against the preparation toinsert it into an intestinal wall.

The PN-protein may be selected from an immunoglobulin molecule orfunctional variants thereof known in the art, with such variantsretaining the characteristic binding property of the PCSK9 bindingprotein. Examples of specific immunoglobulin molecules which may be usedinclude, but are not limited to, an scFv (single chain variablefragment); a monoclonal antibody; a human antibody; a chimeric antibody;a humanized antibody; a single domain antibody; a Fab (fragment antigenbinding) fragment; an Fab′ fragment; an F(ab′)2; an Fv (variablefragment); a disulfide linked Fv, and a bispecific or dual specificantibody. Preferably, the binding protein is a human antibody and/or amonoclonal antibody.

One or more of the immunoglobulin molecules described herein willtypically, though not necessarily, comprise 2 heavy (H) chains and 2light (L) chains interconnected by disulfide bonds. The amino terminalportion of each chain includes a variable region of about 100-110 aminoacids primarily responsible for antigen recognition via thecomplementarity determining regions (CDRs) contained therein. Thecarboxy-terminal portion of each chain defines a constant regionprimarily responsible for effector function. Light chains are classifiedas kappa or lambda, which are each characterized by a particularconstant region as known in the art. Heavy chains are classified asgamma, mu, alpha, delta, or epsilon, and define the isotype of anantibody as IgG, IgM, IgA, IgD, or IgE, respectively. IgG antibodies canbe further divided into subclasses, e.g., IgG1, IgG2, IgG3, IgG4. Eachheavy chain type is also characterized by a particular constant regionwith a sequence well known in the art. “Antigen-binding fragment”, asused herein, refers to Fab fragments, Fab′ fragments, F(ab′)₂ fragments,and single chain Fv fragments one more of which bind to human PCSK9. Theterm “bind (or ‘binds’) to human PCSK9”, as used herein, refers tointeraction with an epitope on human PCSK9. The term “epitope” as usedherein refers to discrete, three-dimensional sites on an antigen thatare recognized by the antibodies or antigen-binding fragments of theinvention.

Another aspect of the invention provides a PCSK9 neutralizing proteincomprising any one of the binding proteins disclosed herein (e.g.,AP-antibodies and AP-antibodies such as Secukinumab) wherein the PCSK9neutralizing binding protein is capable of neutralizing and/orinhibiting the biologic effects of one more of PCSK9 molecules bypreventing or diminishing the ability of the selected PCSK9 from bindingto a receptor for that PCSK9. Such a neutralizing effect can be achievedby selecting the binding protein to either: 1) bind to the selectedPCSK9 so as prevent or inhibit that PCSK9 from binding to the receptorfor that PCSK9 and in turn causing one or more biological effects; or 2)bind to a receptor for that particular PCSK9 so as to prevent the PCSK9from activating the receptor and causing the one or more biologiceffects

In many embodiments, the dose of the selected AP-antibody or otherPN-protein delivered by embodiments of the swallowable capsule describedherein, though it is contemplated that other swallowable devices can beused. The dose of the selected AP-antibody can be titrated to treat acholesterol or lipid related condition (e.g. hypercholesterolemia,dyslipidemia) while minimizing the adverse effect associated with aninjected dose (e.g. intravenous, intramuscular, subcutaneous etc.) ofthe antibody. Such adverse effects can include without limitation one ormore of anaphylactic shock or other allergic reaction (e.g., edema,water eyes, respiratory congestion), immunogenic reaction to thePN-protein (including immunogenic neutralization of the deliveredPN-protein by patients own antibodies), headache, fever and otherrelated effect. In particular embodiments, this can be achieved bytitrating the delivered dose of AP-antibody or other PN-protein to adaily vs a monthly dose which is typically given for AP-antibodies. Forthe case of minimizing immune response, this result can also be achievedby delivering the dose of AP-antibodies to the upper or mid portion ofthe small intestine and avoiding the lower section of the intestinee.g., the ileum containing the Peyer's patches as is discussed infurther detail herein. Other benefits of delivering the AP-antibody insmaller doses into the small intestine (vs. by injection) include one ormore of the following: i) higher therapeutic ratios; and ii) reducedfluctuation (known as % steady state fluctuation as is described in moredetail herein) in the plasma concentration for the AP-antibody or otherPN protein.

In another aspect, the invention provides methods for reducing LDL-Clevels in a patient having elevated LDL-C levels, comprisingadministering to the patient a therapeutically effective amount of anAP-antibody using one or more embodiments of the swallowable capsuledescribed herein, thereby reducing LDL-C levels. The invention alsoprovides methods for reducing LDL-C levels in a patient comprisingselecting a patient having elevated LDL-C levels (determined by one ormore methods known in the art), and administering to the patient atherapeutically effective amount of an AP-antibody using one or moreembodiments of the swallowable capsule described herein (or any otherswallowable device or pill). LDL-cholesterol levels and or lipids can bemonitored to determine the efficacy of treatments in lowering LDL-Clevels and if necessary, adjustments can be made in the dosage (e.g.increase of decrease) and/or dose frequency of the administeredAP-antibody

Related aspects of the invention provide methods for treatingatherosclerosis in a patient, comprising: selecting a patient diagnosedwith atherosclerosis, administering to the patient a therapeuticallyeffective amount of an AP-antibody using an embodiment of theswallowable capsule descried herein, and monitoring the patient's levelof atherosclerosis (e.g. using various imaging modalities and/or viacardiac catheterization). Also provided are methods for reducingcoronary heart disease risk, comprising: selecting a patient havingelevated LDL-C and/or lipid levels and one or more additional indicatorsof coronary heart disease, administering to the patient atherapeutically effective amount of an antisense compound targeted toone or more PCSK9 nucleic acids, and monitoring LDL-C levels and/orlipid levels and adjusting the dose of antisense compound accordingly.Additionally, provided are methods for treating hypercholesterolemia,dyslipidemia or other related condition comprising administering to apatient diagnosed with hypercholesterolemia and/or dyslipidemia atherapeutically effective amount of an antisense oligonucleotidetargeted to a PCSK9 nucleic acid, thereby reducing cholesterol and/orlipid levels. In these and related embodiments, the AP-antibody maycorrespond to one more of Alirocumab, Evolocumab or Bococizumab theiranalogues and derivatives as well as antigen-binding portions thereof.In additional or supplemental embodiments, genetic testing can beperformed on the patient prior to AP-antibody administration todetermine the most effective of these or other AP antibody to use(and/or those that may have an adverse reaction) and/or the mosteffective dosage and/or dose frequency.

In another aspect, the invention provides methods for treating a diseaseor condition associated with the biological activity of a PCSK9 moleculeincluding various forms of dyslipidemia and/or hypercholesterolemiaincluding, without limitation, heterozygous familialhypercholesterolemia, and homozygous familial hypercholesterolemia. Themethod comprises providing a solid anti-PCSK9 antibody (AP-antibody)dosage shaped as a tissue penetrating member which may be dart like orneedle shaped with other shapes and/or structures contemplated as well.The dosage is orally delivered to the small intestine by mean of anorally ingested swallowable capsule or other swallowable device. Once inthe small intestine (or other location in the intestinal tract), thesolid dosage penetrates and is inserted into the intestinal wall by theapplication of a mechanical force or other force on the tissuepenetrating member such that the tissue penetrating member is retainedin the intestinal wall. A therapeutically effective dose of theAP-antibody is then released into the blood stream from the solid dosageAP-antibody in the intestinal wall to inhibit the activity of PCSK9molecule and thereby treat the diseases or condition. In these andrelated embodiments, the AP-antibody may correspond to one more ofAlirocumab, Evolocumab or Bococizumab as well as antigen-bindingportions thereof along with the analogues and derivatives of theaforementioned AP-antibodies.

In other aspects, the invention provides a method for deliveringtherapeutic agents into the wall of the small intestine and/orsurrounding tissue such as the peritoneum comprising swallowing a drugdelivery device comprising a capsule, an actuator and an embodiment ofthe therapeutic agent preparation such as a INP preparation (e.g. apreparation comprising one or more anti-PCSK9 antibodies). The actuatoris responsive to a condition in the small intestine such as pH so as toactuate delivery of the therapeutic agent preparation into the wall ofthe small intestine and/or surrounding tissue such as the wall of theperitoneum. In specific embodiments, the actuator can comprise a releaseelement or coating on the capsule which is degraded by a selected pH inthe small intestine. Once degraded, the element or coating initiatesdelivery of the therapeutic agent preparation by one or more deliverymeans such as the by expansion of one or more balloons that are operablycoupled to tissue penetrating members that contain the therapeutic agentpreparation and are configured to penetrate and be advanced into theintestinal wall upon expansion of the balloon. Once the tissuepenetrating members are in the intestinal wall, they degrade to releasethe therapeutic agent into the bloodstream. Because the therapeuticagent preparation is delivered directly into the wall of the smallintestine (and or surrounding tissue such as the peritoneum), the timeperiod (described herein as t_(max)) for achieving the maximumconcentration of the IBO or other therapeutic agent in the bloodstreamor other location in the body is shorter than a corresponding timeperiod for achieving such a maximum concentration when the therapeuticagent is non-vascularly injected into the body such as by intramuscularor subcutaneous injection. In various embodiments, the time period forachieving C_(max) by insertion of the therapeutic preparation into theintestinal wall using one or more embodiments of the invention (such asan embodiment of the swallowable device) can be about 80%, 50%, 30%, 20or even 10% of the time period for achieving a C_(max) through the useof a non-vascular injection of the therapeutic agent. As used herein theterm about generally refers to within 5% of the stated value of anumber, but in some cases may larger of smaller. In other embodiments,the C_(max) achieved by insertion of the therapeutic preparation intothe intestinal wall using one or more embodiments of the invention, suchas an embodiment of the swallowable device, can be greater than aC_(max) achieved by taking a conventional oral form of the therapeuticagent (e.g., a pill) where the therapeutic agent is not inserted intothe intestinal wall. In various embodiments, the C_(max) achieved byinsertion of the therapeutic preparation into the intestinal wall usingone or more embodiments of the invention (such as an embodiment of theswallowable device) can be 5, 10, 20, 30, 40, 50, 60, 70, 80 or even a100 times greater than when the therapeutic agent is delivered in a pillor other oral form. In other related embodiments, the composition can beconfigured to produce a long-term release of therapeutic agent with aselectable t½, (that is the time period required for the concentrationof the therapeutic agent in the bloodstream or other location in thebody to reach half its original C_(max) value after having reachedC_(max)). For example, the selectable t½ may be 6, or 9, or 12, or 15 or18, or 24 hours.

In another aspect, the invention provides a swallowable device fordelivering a drug or other therapeutic agent preparation into the wallof the small or large intestine, peritoneum or other organ of thegastro-intestinal tract organ. The devise comprises a capsule sized tobe swallowed and pass through the gastro-intestinal tract, a deployablealigner positioned within the capsule for aligning a longitudinal axisof the capsule with the a longitudinal axis of the small intestine, adelivery mechanism for delivering the therapeutic agent into theintestinal wall and a deployment member for deploying at least one ofthe aligner or the delivery mechanism. The capsule wall is degradable bycontact with liquids in the GI tract but also may include an outercoating or layer which only degrades in the higher pH found in the smallintestine, and serves to protect the underlying capsule wall fromdegradation within the stomach before the capsule reaches the smallintestine at which point the drug delivery is initiated by degradationof the coating. In use, such materials allow for the targeted deliveryof a therapeutic agent in a selected portion of the intestinal tractsuch as the small intestine. Suitable outer coatings can include variousenteric coatings such as various co-polymers of acrylic acid (aparticular example including EUDRAGIT available from EVONIK industries),Methacrylic Acid and Ethyl Acrylate. In particular embodiments, theouter coating can be configured to degrade in the pH found in the upperportion of the small intestine (e.g. the duodenum) or mid portions(jejunum) such that therapeutic agent preparation is delivered into thatrespective portion and avoids the lower portion of the small intestine(the ileum) containing the Peyer's patches which are aggregated lymphoidnodules which produce macrophages, and other immune related cells. Inexample of such a coating which degrades in the pH of the duodenum orjejunum can include EUDRAGIT. By delivering the therapeutic agent to alocation in the small intestine without Peyer's patches, the generationof immune related cells and subsequent immune response (e.g. generationof various PCSK9s) to the therapeutic agent is minimized. Thus in use,such controlled placement or delivery of the therapeutic agent into theupper or other select portions of the small intestines, eliminates orotherwise minimizes the immune response of the patient to a particulartherapeutic agent.

Another embodiment of the capsule includes at least one guide tube, oneor more tissue penetrating members positioned in the at least one guidetube, a delivery member and an actuating mechanism. The tissuepenetrating member will typically comprise a hollow needle or other likestructure and will have a lumen and a tissue penetrating end forpenetrating a selectable depth into the intestinal wall. In variousembodiments, the device can include a second and a third tissuepenetrating member with additional numbers contemplated. Each tissuepenetrating member can include the same or a different drug. Inpreferred embodiments having multiple tissue penetrating members, thetissue penetrating members can be symmetrically distributed around theperimeter of the capsule so as to anchor the capsule onto the intestinalwall during delivery of drug. In some embodiments, all or a portion ofthe tissue penetrating member (e.g., the tissue penetrating end) can befabricated from the drug preparation itself. In these and relatedembodiments, the drug preparation can have a needle, dart-like or otherelongated structure with a pointed end (with or without barbs)configured to penetrate and be retained in the intestinal wall.

The tissue penetrating member can be fabricated from variousbiodegradable materials so as to degrade within the small intestine andthus provide a fail-safe mechanism for detaching the tissue penetratingmember from the intestinal wall should this component become retained inthe intestinal wall. Such biodegradable materials may correspond to oneor more of, PGLA, maltose or other sugar, polyethylene, polyethyleneoxide or other biodegradable polymer known in the art. Additionally, intheses and related embodiments, selectable portions of the capsule canbe fabricated from such biodegradable materials so as to allow theentire device to controllably degrade into smaller pieces. Suchembodiments facilitate passage and excretion of the devices through theGI tract. In particular embodiments, the capsule can include seams ofbiodegradable material which controllably degrade to produce capsulepieces of a selectable size and shape to facilitate passage through theGI tract. The seams can be pre-stressed, perforated or otherwise treatedto accelerate degradation. The concept of using biodegradable seams toproduce controlled degradation of a swallowable device in the GI tractcan also be applied to other swallowable devices such as swallowablecameras to facilitate passage through the GI tract and reduce thelikelihood of a device becoming stuck in the GI tract.

The delivery member is configured to advance the drug from the capsulethrough the tissue penetrating member lumen and into the intestinalwall. Typically, at least a portion of the delivery member isadvanceable within the tissue penetrating member lumen. The deliverymember can have a piston or like structure sized to fit within thedelivery member lumen. The distal end of the delivery member (the endwhich is advanced into tissue) can have a plunger element which advancesthe drug within tissue penetrating member lumen and also forms a sealwith the lumen. The plunger element can be integral or attached to thedelivery member. Preferably, the delivery member is configured to travela fixed distance within the needle lumen so as to deliver a fixed ormetered dose of drug into the intestinal wall. This can be achieved byone or more of the selection of the diameter of the delivery member(e.g., the diameter can be distally tapered), the diameter of the tissuepenetrating member (which can be narrowed at its distal end), use of astop, and/or the actuating mechanism. For embodiments of the devicehaving a tissue penetrating member fabricated from drug (e.g., a drugdart), the delivery member is adapted to advance the dart out of thecapsule and into tissue.

The delivery member and tissue penetrating member can be configured forthe delivery of liquid, semi-liquid or solid forms of drug or all three.Solid forms of drug can include both powder or pellet. Semi liquid caninclude a slurry or paste. The drug can be contained within a cavity ofthe capsule, or in the case of the liquid or semi-liquid, within anenclosed reservoir. In some embodiments, the capsule can include a firstsecond, or a third drug (or more). Such drugs can be contained withinthe tissue penetrating member lumen (in the case of solids or powder) orin separate reservoirs within the capsule body.

The actuating mechanism can be coupled to at least one of the tissuepenetrating member or the delivery member. The actuating mechanism isconfigured to advance the tissue penetrating member a selectabledistance into the intestinal wall as well as advance the delivery memberto deliver the drug and then withdraw the tissue penetrating member fromthe intestinal wall. In various embodiments, the actuating mechanism cancomprise a preloaded spring mechanism which is configured to be releasedby the release element. Suitable springs can include both coil(including conical shaped springs) and leaf springs with other springstructures also contemplated. In particular embodiments, the spring canbe cone shaped to reduce the length of the spring in the compressedstate even to the point where the compressed length of the spring isabout the thickness of several coils (e.g., two or three) or only onecoil.

In particular embodiments, the actuating mechanism comprises a spring, afirst motion converter, and a second motion converter and a trackmember. The release element is coupled to the spring to retain thespring in a compressed state such that degradation of the releaseelement releases the spring. The first motion converter is configured toconvert motion of the spring to advance and withdraw the tissuepenetrating element in and out of tissue. The second motion converter isconfigured to convert motion of the spring to advance the deliverymember into the tissue penetrating member lumen. The motion convertersare pushed by the spring and ride along a rod or other track memberwhich serves to guide the path of the converters. They engage the tissuepenetrating member and/or delivery member (directly or indirectly) toproduce the desired motion. They are desirably configured to convertmotion of the spring along its longitudinal axis into orthogonal motionof the tissue penetrating member and/or delivery member thoughconversion in other directions is also contemplated. The motionconverters can have a wedge, trapezoidal or curved shape with othershapes also contemplated. In particular embodiments, the first motionconverter can have a trapezoidal shape and include a slot which engagesa pin on the tissue penetrating member that rides in the slot. The slotcan have a trapezoidal shape that mirrors or otherwise corresponds tothe overall shape of the converter and serves to push the tissuepenetrating member during the upslope portion of the trapezoid and thenpull it back during the down slope portion. In one variation, one orboth of the motion converters can comprise a cam or cam like devicewhich is turned by the spring and engages the tissue penetrating and/ordelivery member.

In other variations, the actuating mechanism can also comprise anelectro-mechanical device/mechanism such as a solenoid or apiezoelectric device. In one embodiment, the piezoelectric device cancomprise a shaped piezoelectric element which has a non-deployed anddeployed state. This element can be configured to go into the deployedstate upon the application of a voltage and then return to thenon-deployed state upon the removal of the voltage. This and relatedembodiments allow for a reciprocating motion of the actuating mechanismso as to both advance the tissue penetrating member and then withdrawit.

The release element is coupled to at least one of the actuatingmechanism or a spring coupled to the actuating mechanism. In particularembodiments, the release element is coupled to a spring positionedwithin the capsule so as to retain the spring in a compressed state.Degradation of the release element releases the spring to actuate theactuation mechanism. In many embodiments, the release element comprisesa material configured to degrade upon exposure to chemical conditions inthe small or large intestine such as pH. Typically, the release elementis configured to degrade upon exposure to a selected pH in the smallintestine, e.g., about 7.0, 7.1, 7.2, 7.3, 7.4, 8.0 or greater. However,it can also be configured to degrade in response to other conditions inthe small intestine e.g. osmolality, fluid content of the smallintestine contents, viscosity of contents, flora, compressive forces,presence and/or concentration of various bile salts and the line. Inparticular embodiments, the release element can be configured to degradein response to particular chemical conditions in the fluids in the smallintestine such as those which occur after ingestion of a meal (e.g., ameal high in fats or proteins).

Biodegradation of the release element from one or more conditions (e.g.pH, osmolality, presence of bile salts, etc.) in the small intestine (orother location in the GI tract) can be achieved by selection of thematerials for the release element, the amount of cross linking of thosematerials as well as the thickness and other dimensions of the releaseelements. Lesser amounts of cross linking and or thinner dimensions canincrease the rate of degradation and vice versa. Suitable materials forthe release element can comprise biodegradable materials such as variousenteric materials which are configured to degrade upon exposure to thehigher pH or other condition in the small intestine. The entericmaterials can be copolymerized or otherwise mixed with one or morepolymers to obtain a number of particular material properties inaddition to biodegradation. Such properties can include withoutlimitation stiffness, strength, flexibility and hardness.

In particular embodiments, the release element can comprise a film orplug that fits over or otherwise blocks the guide tube and retains thetissue penetrating member inside the guide tube. In these and relatedembodiments, the tissue penetrating member is coupled to a spring loadedactuating mechanism such that when the release element is degradedsufficiently, it releases the tissue penetrating member which thensprings out of the guide tube to penetrate into the intestinal wall. Inother embodiments, the release element can be shaped to function as alatch which holds the tissue penetrating element in place. In these andrelated embodiments, the release element can be located on the exterioror the interior of the capsule. In the interior embodiments, the capsuleand guide tubes are configured to allow for the ingress of intestinalfluids into the capsule interior to allow for the degradation of therelease element.

In some embodiments, the actuating mechanism can be actuated by means ofa sensor, such as a pH or other chemical sensor which detects thepresence of the capsule in the small intestine and sends a signal to theactuating mechanism (or to an electronic controller coupled to theactuating mechanism to actuate the mechanism). Embodiments of a pHsensor can comprise an electrode-based sensor or it can be amechanically-based sensor such as a polymer which shrinks or expandsupon exposure to the pH or other chemical conditions in the smallintestine. In related embodiments, an expandable/contractable sensor canalso comprise the actuating mechanism itself by using the mechanicalmotion from the expansion or contraction of the sensor.

According to another embodiment for detecting that the device is in thesmall intestine (or other location in the GI tract), the sensor cancomprise a strain gauge or other pressure/force sensor for detecting thenumber of peristaltic contractions that the capsule is being subject towithin a particular location in the intestinal tract. In theseembodiments, the capsule is desirably sized to be gripped by the smallintestine during a peristaltic contraction). Different locations withinthe GI tract have different number of peristaltic contractions. Thesmall intestine has between 12 to 9 contractions per minute with thefrequency decreasing down the length of the intestine. Thus, accordingto one or more embodiments detection of the number of peristalticcontractions can be used to not only determine if the capsule is in thesmall intestine but the relative location within the intestine as well.

As an alternative or supplement to internally activated drug delivery,in some embodiments, the user may externally activate the actuatingmechanism to deliver drug by means of RF (radio frequency), magnetic orother wireless signaling means known in the art. In these and relatedembodiments, the user can use a handheld device (e.g., a hand held RFdevice) which not only includes signaling means, but also means forinforming the user when the device is in the small intestine or otherlocation in the GI tract. The later embodiment can be implemented byincluding an RF transmitter on the swallowable device to signal to theuser when the device is in the small intestine or other location (e.g.,by signaling an input from the sensor). The same handheld device canalso be configured to alert the user when the actuating mechanism hasbeen activated and the selected drug(s) delivered. In this way, the useris provided confirmation that the drug has been delivered. In anotherapproach an external acoustical sensor can be used to detect when theactuating mechanism has been activated by detecting sounds unique to theactuating mechanism be activated, for example, by detecting one or moreeigen frequency sounds which can occur for embodiments using a chamberincluding a piston and cylinder mechanism operably coupled to the tissuepenetrating member. One or more of the preceding approaches allow theuser to take other appropriate drugs/therapeutic agents as well as makeother related decisions (e.g., for diabetics to eat a meal or not andwhat foods should be eaten). The handheld device can also be configuredto send a signal to the swallowable device to over-ride the actuatingmechanism and so prevent, delay or accelerate the delivery of drug. Inuse, such embodiments allow the user to intervene to prevent, delay oraccelerate the delivery of drug based upon other symptoms and/or patientactions (e.g., eating a meal, deciding to go to sleep, exercise etc.).

The user may also externally activate the actuating mechanism at aselected time period after swallowing the capsule. The time period canbe correlated to a typical transit time or range of transit times forfood moving through the user's GI tract to a particular location in thetract such as the small intestine. External activation can be done byany number of means including radio control means (e.g. using an RFcommunication device), magnetic means (e.g. by use of miniature magneticswitch or release built into the swallowable device that the useractivates with an external magnetic) or acoustic means (e.g. via anultrasonic transmission device and an acoustical receive and/or switchbuilt into the swallowable device)

Another aspect of the inventions provides therapeutic agent preparationsfor delivery into the wall of the small intestine (including surroundingtissue such as the peritoneum) or other wall in the intestinal tractusing embodiments of the swallowable device described herein. Thepreparation comprises a therapeutically effective dose of at least onetherapeutic agent such as antibody or other binding protein. Also, itmay comprise a solid, liquid or combination of both and can include oneor more pharmaceutical excipients. The preparation has a shape andmaterial consistency to be contained in embodiments of the swallowablecapsule, delivered from the capsule into the intestinal wall and/orperitoneal wall or other surrounding tissue) and degrade within theintestinal/peritoneal wall to release the dose of therapeutic agent. Thepreparation may also have a selectable surface area to volume ratio soas enhance or otherwise control the rate of degradation of thepreparation in the wall of the small intestine, peritoneal wall or otherbody lumen. In various embodiments, the preparation can be configured tobe coupled to an actuator such as a release element or actuationmechanism which has a first configuration in which the preparation iscontained in the capsule and a second configuration in which thepreparation is advanced out of the capsule and into the wall of thesmall intestine and/or peritoneum. The dose of the drug or othertherapeutic agent in the preparation can be titrated downward from thatwhich would be required for conventional oral delivery methods so thatpotential side effects from the drug can be reduced.

Typically, though not necessarily, the preparation will be shaped andotherwise configured to be contained in the lumen of a tissuepenetrating member, such as a hollow needle, which is configured to beadvanced out of the capsule and into the wall of the small intestineand/or peritoneal wall. The preparation itself may comprise a tissuepenetrating member configured to be advanced into the wall of the smallintestine and/or peritoneal wall, or other lumen in the intestinaltract. Such configurations of the tissue penetrating member may includevarious shapes having a pointed tip including for example, needles,darts, and other like shapes. In particular embodiments the tissuepenetrating member comprises various elongated shapes having a pointedend. It may also comprise various isometric shapes having a pointed end,such as a triangle, square with pointed end, conical with a pointed end,or hemispherical with a pointed end.

Another aspect of the invention provides methods for the delivery ofdrugs and the therapeutic agents into the walls of the GI tract usingembodiments of the swallowable drug delivery devices. Such methods canbe used for the delivery of therapeutically effective amounts of avariety of drugs and other therapeutic agents. These include a number oflarge molecule peptides and proteins which would otherwise requireinjection due to chemical breakdown in the stomach e.g., antibodiesgrowth hormone, parathyroid hormone, insulin, interferons and other likecompounds. Suitable drugs and other therapeutic agents which can bedelivered by embodiments of invention include various antibodies (e.g.,anti-PCSK9 antibodies, TNF inhibiting class of antibodies,chemotherapeutic agents (e.g., interferon), antibiotics, antivirals,insulin and related compounds, glucagon like peptides (e.g., GLP-1,exenatide), parathyroid hormones, growth hormones (e.g., IFG and othergrowth factors), anti-seizure agents, immune suppression agents andanti-parasitic agents such as various anti-malarial agents. The dosageof the particular drug can be titrated for the patient's weight, age,condition or other parameter.

In various method embodiments of the invention, embodiments of the drugswallowable drug delivery device can be used to deliver a plurality ofdrugs for the treatment of multiple conditions or for the treatment of aparticular condition (e.g., a mixture of protease inhibitors fortreatment HIV AIDS). In use, such embodiments allow a patient to forgothe necessity of having to take multiple medications for a particularcondition or conditions. Also, such embodiments provide a means forensuring that a regimen of two or more drugs is delivered and absorbedinto the small intestine and thus, the blood stream at about the sametime. Due to differences in chemical makeup, molecular weight, etc.,drugs can be absorbed through the intestinal wall at different rates,resulting in different pharmacokinetic distribution curves. Embodimentsof the invention address this issue by injecting the desired drugmixtures at about the same time. This in turn improves (e.g. bysubstantially synchronizing e.g., within 5% in time) the pharmacokineticparameters for the mixture of the selected drugs (e.g., by achievingsimilar t_(1/2)'s for different drugs) and thus, the efficacy of theselected mixture of drugs.

In another aspect, various embodiment of the invention providepharmaceutical compositions comprising solid shaped masses comprising adrug such as an antibody or other immunglobulin having a biologicalactivity (e.g. binding affinity for an antigen) in the body of a mammalwherein at least a portion of the biological activity of the antibody ismaintained after formation of the shape mass from a precursor materialsuch as powder. The biological activity may be correlated to thestructural integrity of the antibody or other drug post formation (e.g.by correlating bioactivity assays to chemical assays), such that on acompositional level, a selected percentage of the antibody (e.g., on aweight basis) is maintained post formation relative to that in theprecursor material. Typically, the shape will be formed by a compressionprocess (e.g. compression molding), though other processes are alsocontemplated such as non compressive molding. The drug may correspond toa peptide, antibody, immunglobulin or other protein wherein thebiological activity of the drug in the shaped mass is at least 70% tothat prior to compression and more preferably, at least 90% to thatprior to compression and still more preferably at least 95%. Thesenumbers may also correspond to a weight percentage of the drug remainingin the shaped mass relative to that in the precursor material (e.g., bycorrelating biological activity assays to chemical assays for weightcomposition as described above). In these and related embodiments, theshaped mass can have a density in a range of about 1.00 and 1.15 mg/mm3and in more preferred embodiments, 1.02 and 1.06 mg/mm3. The shape willtypically comprise a pellet shape but may also have a tablet, conical,cylindrical, cube, sphere or other like shape. Typically the pellet orother form of the shaped mass will then by inserted into an embodimentof the tissue penetrating member described herein.

Embodiments of the invention also provide methods for forming solidshaped masses comprising antibodies, immuglobulins, or other proteinswhere the shaped masses are formed by the shaping of a precursormaterial and where at least a portion of the biological activity (e.gantigen binding affinity, specifity, etc) of the peptide, antibody orother protein in the shaped mass is preserved after formation. In manyembodiments, the shaping is done by compression of the precursormaterial where the compressive forces are selected to minimizedegradation of the biological activity of the protein or polypeptide.Other shaping methods are also contemplated. Typically, the precursormaterial will comprise a powder mixture comprising the drug and one ormore excipients. The precursor material may also comprise a liquid,slurry or paste. The excipients may include one more of a lubricant, abinder, bulking agent, etc. The shaped mass may be in the form of atablet, micro-tablet, pill or slug shape. According to one or moreembodiments, the shaped masses produced using embodiments of theformation process can have another property such as density or particlegrain size (of the powder used to formulate the shaped mass) which iscorrelated to minimum level of bioactivity of the protein or peptide.Also, that correlated property may be may consistently maintained withina selected range within a given lot of shaped masses as well from lot tolot. Embodiments of the solid masses described herein can be configuredto be used in combination with any suitable drug delivery system to beadministered via any appropriate route of administration for thecondition to be treated. Such routes of administration can includewithout limitation, oral, sublingual parenteral, intravenous,intramuscular, intra-ventricular, intra-cardiac, intracranial. Forexample, according to one embodiments, antibody-containing micro-tablets(e.g, a microtablet containing an anti-PCSK9 antibody) can be takenorally and delivered into the small intestine where the antibody isdelivered into the wall of the small intestine and/or peritoneal wallwhere the tablet(s) dissolves to release the antibody into the bloodstream where it binds to the selected target molecule (e.g an PCSK9) totreat one or more conditions (e.g various autoimmune conditions such asrheumatoid arthritis, multiple sclerosis, psoriatis, etc). In anotherembodiment insulin, containing micro tablets can be injected orotherwise placed subcutaneously (e.g. intramuscularly) where theydissolve to release antibody into the bloodstream.

Further details of these and other embodiments and aspects of theinvention are described more fully below, with reference to the attacheddrawing figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1a is a lateral viewing showing an embodiment of a swallowable drugdelivery device.

FIG. 1b is a lateral viewing showing an embodiment of a system includinga swallowable drug delivery device.

FIG. 1c is a lateral viewing showing an embodiment of a kit including aswallowable drug delivery device and a set of instructions for use.

FIG. 1d is a lateral viewing showing an embodiment of a swallowable drugdelivery device including a drug reservoir.

FIG. 2 is a lateral view illustrating an embodiment of the swallowabledrug delivery device having a spring loaded actuation mechanism foradvancing tissue penetrating members into tissue.

FIG. 3 is a lateral view illustrating an embodiment of the swallowabledrug delivery device having a spring loaded actuation mechanism having afirst motion converter.

FIG. 4 is a lateral view illustrating an embodiment of the swallowabledrug delivery device having a spring loaded actuation mechanism havingfirst and a second motion converter.

FIG. 5 is a perspective view illustrating engagement of the first andsecond motion converters with the tissue penetrating member and deliverymembers.

FIG. 6 is a cross sectional view illustrating an embodiment of theswallowable drug delivery device having a single tissue penetratingmember and an actuating mechanism for advancing the tissue penetratingmember.

FIG. 7a is a cross sectional view illustrating an embodiment of theswallowable drug delivery device having multiple tissue penetratingmembers and an actuating mechanism for advancing the tissue penetratingmembers.

FIG. 7b is a cross sectional view illustrating deployment of the tissuepenetrating members of the embodiment of FIG. 7a to deliver medicationto a delivery site and anchor the device in the intestinal wall duringdelivery.

FIGS. 8a-8c are side view illustrating positioning of the drug deliverydevice in the small intestine and deployment of the tissue penetratingmembers to deliver drug; FIG. 8a shows the device in the small intestineprior to deployment of the tissue penetrating members with the releaseelement in tact; FIG. 8b shows the device in the small intestine withthe release element degraded and the tissue penetrating elementsdeployed; and FIG. 8c shows the device in the small intestine with thetissue penetrating elements retracted and the drug delivered.

FIG. 9a shows an embodiment of a swallowable drug delivery deviceincluding a capsule having bio-degradable seams positioned to producecontrolled degradation of the capsule in the GI tract.

FIG. 9b shows the embodiment of FIG. 9a after having been degraded inthe GI tract into smaller pieces.

FIG. 10 shows an embodiment of a capsule having biodegradable seamsincluding pores and/or perforations to accelerate biodegradation of thecapsule.

FIG. 11 is a lateral viewing illustrating use of an embodiment of aswallowable drug delivery device including transit of device in the GItract and operation of the device to deliver drug.

FIGS. 12a and 12b are lateral view illustrating an embodiment of acapsule for the swallowable drug delivery device including a cap and abody coated with pH sensitive biodegradable coatings, FIG. 12a shows thecapsule in an unassembled state and FIG. 12b in an assembled state

FIGS. 13a and 13b illustrate embodiments of unfolded multi balloonassemblies containing a deployment balloon, an aligner balloon, adelivery balloon and assorted connecting tubes; FIG. 13a shows anembodiment of the assembly for a single dome configuration of thedeployment balloon; and FIG. 13b shows an embodiment of the assembly fordual dome configuration of the deployment balloon; and.

FIG. 13c is a perspective views illustrating embodiments of a nestedballoon configuration which can be used for one or more embodiments ofthe balloons described herein including the aligner balloon.

FIGS. 14a-14c are lateral views illustrating embodiments of a multicompartment deployment balloon; FIG. 14a shows the balloon in anon-inflated state with the separation valve closed; FIG. 14b shows theballoon with valve open and mixing of the chemical reactants; and FIG.14c shows the balloon in an inflated state.

FIGS. 15a-15g are lateral views illustrating a method for folding of themultiple balloon assembly, the folding configuration in each figureapplies to both single and dual dome configurations of the deploymentballoon, with the exception that FIG. 15c , pertains to a folding stepunique to dual dome configurations; and FIG. 15d , pertains to the finalfolding step unique to dual dome configurations; FIG. 15e , pertains toa folding step unique to single dome configurations; and FIGS. 15f and15g are orthogonal views pertaining to the final folding step unique tosingle dome configurations.

FIGS. 16a and 16b are orthogonal views illustrating embodiments of thefinal folded multi balloon assembly with the attached delivery assembly.

FIGS. 17a and 17b are orthogonal transparent views illustratingembodiments of the final folded multi balloon assembly inserted into thecapsule.

FIG. 18a is a side view of an embodiment of the tissue penetratingmember.

FIG. 18b is a bottom view of an embodiment of the tissue penetratingmember illustrating placement of the tissue retaining features.

FIG. 18c is a side view of an embodiment of the tissue penetratingmember having a trocar tip and inverted tapered shaft.

FIG. 18d is a side view of an embodiment of the tissue penetratingmember having a separate drug containing section.

FIGS. 18e and 18f are side views showing assembly of an embodiment of atissue penetrating member having a shaped drug containing section. FIG.18e shows the tissue penetrating member and shaped drug section prior toassembly; and FIG. 18f after assembly.

FIG. 19 provides assorted views of the components and steps used toassemble an embodiment of the delivery assembly.

FIGS. 20a-20i provide assorted views illustrating a method of operationof an embodiment of the swallowable device to deliver medication to theintestinal wall.

FIG. 21 is a table illustrating various information for PCSK9s,including PCSK9s configured to be bound and/or neutralized by one ormore antibodies provided by embodiments of the invention.

FIGS. 22a and 22b are simulated plasma concentration profiles forAlirocumab delivered daily by embodiments of the swallowable capsule(FIG. 22b ) and monthly by injection using conventional means (FIG. 22a).

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the invention provide devices, systems and methods fordelivering medications in to various locations in the body as well astherapeutic compositions comprising the medication. As used herein, theterm “medication” refers to a medicinal preparation in any form whichcan include one more drugs or other therapeutic agent as well as one ormore pharmaceutical excipients. Many embodiments provide a swallowabledevice for delivering medication within the GI tract. Particularembodiments provide a swallowable device such as a capsule fordelivering medications into the wall of the small intestine and/orperitoneal wall or other GI organ. As used herein, “GI tract” refers tothe esophagus, stomach, small intestine, large intestine and anus, while“Intestinal tract” refers to the small and large intestine. Particularembodiments also provide therapeutics preparations for delivery into thewall of the GI tract comprising a therapeutically effective dose of atleast one PCSK9 neutralizing protein (PN protein or PNP also known as aPCSK9 binding protein or PB-protein) such as an antibody which binds toPCSK9 molecules (herein anti-PCSK9 antibodies or AP-antibodies) or itsreceptors along with their respective analogues and derivatives. Variousembodiments of the invention can be configured and arranged for deliveryof medication into the intestinal tract as well as the entire GI tract.Also, as used herein, the term “about” means within 10% of a givenstated numerical value for a parameter, variable, dimension, and thelike (e.g., a pharmacokinetic parameter such as t_(1/2), t_(max),c_(max), etc.).

Referring now to FIGS. 1-11, an embodiment of a device 10 for thedelivery of medication 100 to a delivery site DS in the intestinal tractsuch as the of the small intestine and/or peritoneal wall, comprises acapsule 20 including at least one guide tube 30, one or more tissuepenetrating members 40 positioned or otherwise advanceable in the atleast one guide tube, a delivery member 50, an actuating mechanism 60and release element 70. Medication 100, also described herein aspreparation 100, typically comprises at least one drug or therapeuticagent 101 and may include one or more pharmaceutical excipients known inthe art. Collectively, one or more of delivery member 50 and mechanism60 may comprise a means for delivery of medication 100 into a wall ofthe intestinal tract. Other delivery means contemplated herein includeone or more expandable balloons (e.g., delivery balloon 172) or otherexpandable device/member described herein.

Device 10 can be configured for the delivery of liquid, semi-liquid orsolid forms of medication 100 or all three. Solid forms ofmedication/preparation 100 can include both powder and pellet. Semiliquid forms can include a slurry or paste. Whatever the form,preparation 100 desirably has a shape and material consistency allowingthe medication to be advanced out of the device, into the intestinalwall (or other luminal wall in the GI tract) and then degrade in theintestinal wall to release the drug or other therapeutic agent 101 whichin various embodiments may correspond to one or more Anti-PCSK9antibodies (or other PCSK9 neutralizing proteins) described herein. Thematerial consistency can include one or more of the hardness, porosityand solubility of the preparation (in body fluids). The materialconsistency can be achieved by one or more of the following: i) thecompaction force used to make the preparation; ii) the use of one ormore pharmaceutical disintegrants known in the art; iii) use of otherpharmaceutical excipients; iv) the particle size and distribution of thepreparation (e.g., micronized particles); and v) use of micronizing andother particle formation methods known in the art. Suitable shapes forpreparation 100 can include cylindrical, cubical, rectangular, conical,spherical, hemispherical and combinations thereof. Also, the shape canbe selected so as to define a particular surface area and volume ofpreparation 100 and thus, the ratio between the two. The ratio ofsurface area to volume can in turn, be used to achieve a selected rateof degradation within the intestinal or other lumen wall within the GItract. Larger ratios (e.g., larger amounts of surface area per unitvolume) can be used to achieve faster rates of degradation and viceversa. In particular embodiments, the surface area to volume ratio canbe in the range of about 1:1 to 100:1, with specific embodiments of 2:1,5:1, 20:1, 25:1, 50:1 and 75:1 (about being within 5%).Preparation/medication 100 will typically be pre-packed within a lumen44 of tissue penetrating members 40, but can also be contained atanother location within an interior 24 of capsule 20, or in the case ofa liquid or semi-liquid, within an enclosed reservoir 27. The medicationcan be pre-shaped to fit into the lumen or packed for example, in apowder form. Typically, the device 10 will be configured to deliver asingle drug 101 as part of medication 100. However in some embodiments,the device 10 can be configured for delivery of multiple drugs 101including a first second, or a third drug which can be compounded into asingle or multiple medications 100. For embodiments having multiplemedications/drugs, the medications can be contained in separate tissuepenetrating members 40 or within separate compartments or reservoirs 27within capsule 20. In another embodiment, a first dose 102 of medication100 containing a first drug 101 can be packed into the penetratingmember(s) 40 and a second dose 103 of medication 100 (containing thesame or a different drug 101) can be coated onto the surface 25 ofcapsule as is shown in the embodiment of FIG. 1b . The drugs 101 in thetwo doses of medication 102 and 103 can be the same or different. Inthis way, a bimodal pharmacokinetic release of the same or differentdrugs can be achieved. The second dose 103 of medication 100 can have anenteric coating 104 to ensure that it is released in the small intestineand achieve a time release of the medication 100 as well. Entericcoating 104 can include one or more enteric coatings described herein orknown in the art.

A system 11 for delivery of medication 100 into the wall of the smallintestine and/or peritoneal wall or other location within the GI tract,may comprise device 10, containing one or more medications 100 for thetreatment of a selected condition or conditions. In some embodiments,the system may include a hand held device 13, described herein forcommunicating with device 10 as is shown in the embodiment of FIG. 1b .System 11 may also be configured as a kit 14 including system 11 and aset of instructions for use 15 which are packaged in packaging 12 as isshown in the embodiment of FIG. 1c . The instructions can indicate tothe patient when to take the device 10 relative to one or more eventssuch as the ingestion of a meal or a physiological measurement such asblood glucose, cholesterol, etc. In such embodiments, kit 14 can includemultiple devices 10 containing a regimen of medications 100 for aselected period of administration, e.g., a day, week, or multiple weeksdepending upon the condition to be treated.

Capsule 20 is sized to be swallowed and pass through the intestinaltract. The size can also be adjusted depending upon the amount of drugto be delivered as well as the patient's weight and adult vs. pediatricapplications. Capsule 20 includes an interior volume 24 and an outersurface 25 having one or more apertures 26 sized for guide tubes 30. Inaddition to the other components of device 10, (e.g., the actuationmechanism etc.) the interior volume can include one or more compartmentsor reservoirs 27. One or more portions of capsule 20 can be fabricatedfrom various biocompatible polymers known in the art, including variousbiodegradable polymers which in a preferred embodiment can comprise PGLA(polylactic-co-glycolic acid). Other suitable biodegradable materialsinclude various enteric materials described herein as well as lactide,glycolide, lactic acid, glycolic acid, para-dioxanone, caprolactone,trimethylene carbonate, caprolactone, blends and copolymers thereof. Asis described in further detail herein, in various embodiments, capsule20 can include seams 22 of bio-degradable material so as to controllablydegrade into smaller pieces 23 which are more easily passed through theintestinal tract. Additionally, in various embodiments, the capsule caninclude various radio-opaque or echogenic materials for location of thedevice using fluoroscopy, ultrasound or other medical imaging modality.In specific embodiments, all or a portion of the capsule can includeradio-opaque/echogenic markers 20 m as is shown in the embodiment ofFIGS. 1a and 1b . In use, such materials not only allow for the locationof device 10 in the GI tract, but also allow for the determination oftransit times of the device through the GI tract.

In preferred embodiments, tissue penetrating members 40 are positionedwithin guide tubes 30 which serve to guide and support the advancementof members 40 into tissue such as the of the small intestine and/orperitoneal wall or other portion of the GI tract. The tissue penetratingmembers 40 will typically comprise a hollow needle or other likestructure and will have a lumen 44 and a tissue penetrating end 45 forpenetrating a selectable depth into the intestinal wall IW. Member 40may also include a pin 41 for engagement with a motion converter 90described herein. The depth of penetration can be controlled by thelength of member 40, the configuration of motion converter 90 describedherein as well as the placement of a stop or flange 40 s on member 40which can, in an embodiment, correspond to pin 41 described herein.Medication 100 will typically be delivered into tissue through lumen 44.In many embodiments, lumen 44 is pre-packed with the desired medication100 which is advanced out of the lumen using delivery member 50 or otheradvancement means (e.g. by means of force applied to a collapsibleembodiment of member 40). As an alternative, medication 100 can beadvanced into lumen 44 from another location/compartment in capsule 20.In some embodiments, all or a portion of the tissue penetrating member40 can be fabricated from medication 100 itself. In these and relatedembodiments, the medication can have a needle or dart-like structure(with or without barbs) or other elongated structure with a pointed endconfigured to penetrate and be retained in the intestinal wall (e.g.,the wall of the small intestine and/or peritoneal wall) after insertion.The dart can be sized and shaped depending upon the medication, dose anddesired depth of penetration into the intestinal wall. Medication 100can be formed into darts, pellets or other shapes using variouscompression molding methods known in the pharmaceutical arts.

In various embodiments, device 10 can include a second 42 and a third 43tissue penetrating member 40 as is shown in the embodiments of FIGS. 7aand 7b , with additional numbers contemplated. Each tissue penetratingmember 40 can be used to deliver the same or a different medication 100.In preferred embodiments, the tissue penetrating members 40 can besubstantially symmetrically distributed around the perimeter 21 ofcapsule 20 so as to anchor the capsule onto the intestinal wall IWduring delivery of medications 100. Anchoring capsule 20 in such a wayreduces the likelihood that the capsule will be displaced or moved byperistaltic contractions occurring during delivery of the medication. Inspecific embodiments, the amount of anchoring force can be adjusted tothe typical forces applied during peristaltic contraction of the smallintestine. Anchoring can be further facilitated by configured some orall of tissue penetrating members 40 to have a curved or arcuate shape.

Delivery member 50 is configured to advance medication 100 through thetissue penetrating member lumen 44 and into the intestinal wall IW.Accordingly, at least a portion of the delivery member 50 is advanceablewithin the tissue penetrating member lumen 44 and thus member 50 has asize and shape (e.g., a piston like shape) configured to fit within thedelivery member lumen 44.

In some embodiments, the distal end 50 d of the delivery member (the endwhich is advanced into tissue) can have a plunger element 51 whichadvances the medication within the tissue penetrating member lumen 44and also forms a seal with the lumen. Plunger element 51 can be integralor attached to delivery member 50. Preferably, delivery member 50 isconfigured to travel a fixed distance within the needle lumen 44 so asto deliver a fixed or metered dose of drug into the intestinal wall IW.This can be achieved by one or more of the selection of the diameter ofthe delivery member (e.g., the diameter can be distally tapered), thediameter of the tissue penetrating member (which can be narrowed at itsdistal end), use of a stop, and/or the actuating mechanism. However insome embodiments, the stroke or travel distance of member 50 can beadjusted in situ responsive to various factors such as one or moresensed conditions in the GI tract. In situ adjustment can be achievedthrough use of logic resource 29 (including controller 29 c) coupled toan electro-mechanical embodiment of actuating mechanism 60. This allowsfor a variable dose of medication and/or variation of the distance themedication is injected into the intestinal wall.

Actuating mechanism 60 can be coupled to at least one of the tissuepenetrating member 40 or delivery member 50. The actuating mechanism isconfigured to advance tissue penetrating member 40 a selectable distanceinto the intestinal wall IW as well as advance the delivery member todeliver medication 100 and then withdraw the tissue penetrating memberfrom the intestinal wall. In various embodiments, actuating mechanism 60can comprise a spring loaded mechanism which is configured to bereleased by release element 70. Suitable springs 80 can include bothcoil (including conical shaped springs) and leaf springs with otherspring structures also contemplated. In particular embodiments, spring80 can be substantially cone-shaped to reduce the length of the springin the compressed state even to the point where the compressed length ofthe spring is about the thickness of several coils (e.g., two or three)or only one coil.

In particular embodiments actuating mechanism 60 can comprise a spring80, a first motion converter 90, and a second motion converter 94 and atrack member 98 as is shown in the embodiments of FIGS. 2, 4 and 8 a-8c. The release element 70 is coupled to spring 80 to retain the springin a compressed state such that degradation of the release elementreleases the spring. Spring 80 may be coupled to release element 70 by alatch or other connecting element 81. First motion converter 90 isconfigured to convert motion of spring 80 to advance and withdraw thetissue penetrating member 40 in and out of the intestinal wall or othertissue. The second motion converter 94 is configured to convert motionof the spring 80 to advance the delivery member 50 into the tissuepenetrating member lumen 44. Motion converters 90 and 94 are pushed bythe spring and ride along a rod or other track member 98 which fits intoa track member lumen 99 of converter 90. The track member 98 serves toguide the path of the converters 90. Converters 90 and 94 engage thetissue penetrating member 40 and/or delivery member 50 (directly orindirectly) to produce the desired motion. They have a shape and othercharacteristics configured to convert motion of the spring 80 along itslongitudinal axis into orthogonal motion of the tissue penetratingmember 40 and/or delivery member 50 though conversion in otherdirections is also contemplated. The motion converters can have a wedge,trapezoidal or curved shape with other shapes also contemplated. Inparticular embodiments, the first motion converter 90 can have atrapezoidal shape 90 t and include a slot 93 which engages a pin 41 onthe tissue penetrating member that rides in the slot as is shown in theembodiments of FIGS. 2, 3 and 4. Slot 93 can also have a trapezoidalshape 93 t that mirrors or otherwise corresponds to the overall shape ofconverter 90. Slot 93 serves to push the tissue penetrating member 40during the upslope portion 91 of the trapezoid and then pull it backduring the down slope portion 92. In one variation, one or both of themotion converters 90 and 94 can comprise a cam or cam like device (notshown). The cam can be turned by spring 80 so as to engage the tissuepenetrating and/or delivery members 40 and 50. One or more components ofmechanism 60 (as well as other components of device 10) including motionconverters 90 and 94 can be fabricated using various MEMS-based methodsknown in the art so as to allow for selected amounts of miniaturizationto fit within capsule 10. Also as is described herein, they can beformed from various biodegradable materials known in the art.

In other variations, the actuating mechanism 60 can also comprise anelectro-mechanical device/mechanism such as a solenoid or apiezoelectric device. In one embodiment, a piezoelectric device used inmechanism 60 can comprise a shaped piezoelectric element which has anon-deployed and deployed state. This element can be configured to gointo the deployed state upon the application of a voltage and thenreturn to the non-deployed state upon the removal of the voltage orother change in the voltage. This and related embodiments allow for areciprocating motion of the actuating mechanism 60 so as to both advancethe tissue penetrating member and then withdraw it. The voltage for thepiezoelectric element can be obtained generated using a battery or apiezoelectric based energy converter which generates voltage bymechanical deformation such as that which occurs from compression of thecapsule 20 by a peristaltic contraction of the small intestine aroundthe capsule. Further description of piezoelectric based energyconverters is found in U.S. patent application Ser. No. 12/556,524 whichis fully incorporated by reference herein for all purposes. In oneembodiment, deployment of tissue penetrating members 40 can in fact betriggered from a peristaltic contraction of the small intestine whichprovides the mechanical energy for generating voltage for thepiezoelectric element.

Release element 70 will typically be coupled to the actuating mechanism60 and/or a spring coupled to the actuating mechanism; however, otherconfigurations are also contemplated. In preferred embodiments, releaseelement 70 is coupled to a spring 80 positioned within capsule 20 so asto retain the spring in a compressed state 85 as shown in the embodimentof FIG. 2. Degradation of the release element 70 releases spring 80 toactuate actuation mechanism 60. Accordingly, release element 70 can thusfunction as an actuator 70 a (actuator 70 may also include spring 80 andother elements of mechanism 60). As is explained further below, releaseelement 70/actuator 70 a has a first configuration where the therapeuticagent preparation 100 is contained within capsule 20 and a secondconfiguration where the therapeutic agent preparation is advanced fromthe capsule into the wall of the small intestine and/or peritoneal wallor other luminal wall in the intestinal tract.

In many embodiments, release element 70 comprises a material configuredto degrade upon exposure to chemical conditions in the small or largeintestine such as pH. Typically, release element 70 is configured todegrade upon exposure to a selected pH in the small intestine, e.g.,7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6 8.0 or greater. The release elementcan also be configured to degrade within a particular range of pH suchas, e.g., 7.0 to 7.5. In particular embodiments, the pH at which releaseelement 70 degrades (defined herein as the degradation pH) can beselected for the particular drug to be delivered so as to release thedrug at a location in small intestine which corresponds to the selectedpH. Further, for embodiments of device 10 having multiple medications100, the device can include a first release element 70 (coupled to anactuating mechanism for delivering a first drug) configured to degradeat first pH and a second release element 70 (coupled to an actuatingmechanism for delivering a second drug) configured to degrade at asecond pH (with additional numbers of release elements contemplated forvarying number of drugs).

Release element 70 can also be configured to degrade in response toother conditions in the small intestine (or other GI location). Inparticular embodiments, the release element 70 can be configured todegrade in response to particular chemical conditions in the fluids inthe small intestine such as those which occur after ingestion of a meal(e.g., a meal containing fats, starches or proteins). In this way, therelease of medication 100 can be substantially synchronized or otherwisetimed with the digestion of a meal.

Various approaches are contemplated for biodegradation of releaseelement 70. In particular embodiments, biodegradation of release element70 from one or more conditions in the small intestine (or other locationin the GI tract) can be achieved by one or more of the followingapproaches: i) selection of the materials for the release element, ii)the amount of cross linking of those materials; and iii) the thicknessand other dimensions of the release element. Lesser amounts of crosslinking and or thinner dimensions can increase the rate of degradationand vice versa. Suitable materials for the release element can comprisebiodegradable materials such as various enteric materials which areconfigured to degrade upon exposure to the higher pH in the intestines.Suitable enteric materials include, but are not limited to, thefollowing: cellulose acetate phthalate, cellulose acetate trimellitate,hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate,carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylicacid methyl esters as well as other enteric materials known in the art.The selected enteric materials can be copolymerized or otherwisecombined with one or more other polymers to obtain a number of otherparticular material properties in addition to biodegradation. Suchproperties can include without limitation stiffness, strength,flexibility and hardness.

In alternative embodiments, the release element 70 can comprise a filmor plug 70 p that fits over or otherwise blocks guide tubes 30 andretains the tissue penetrating member 40 inside the guide tube. In theseand related embodiments, tissue penetrating member 40 is coupled to aspring loaded actuating mechanism such that when the release element isdegraded sufficiently, it releases the tissue penetrating member whichthen springs out of the guide tube to penetrate into the intestinalwall. In still other embodiments, release element 70 can be shaped tofunction as a latch which holds the tissue penetrating member 40 inplace. In these and related embodiments, the release element can belocated on the exterior or the interior of capsule 20. In the lattercase, capsule 20 and/or guide tubes 30 can be configured to allow forthe ingress of intestinal fluids into the capsule interior to allow forthe degradation of the release element.

In some embodiments, actuating mechanism 60 can be actuated by means ofa sensor 67, such as a pH sensor 68 or other chemical sensor whichdetects the presence of the capsule in the small intestine. Sensor 67can then send a signal to actuating mechanism 60 or to an electroniccontroller 29 c coupled to actuating mechanism 60 to actuate themechanism. Embodiments of a pH sensor 68 can comprise an electrode-basedsensor or it can be a mechanically-based sensor such as a polymer whichshrinks or expands upon exposure to a selected pH or other chemicalconditions in the small intestine. In related embodiments, anexpandable/contractible sensor 67 can also comprise the actuatingmechanism 60 itself by using the mechanical motion from the expansion orcontraction of the sensor.

According to another embodiment for detecting that the device in thesmall intestine (or other location in the GI tract), sensor 67 cancomprise pressure/force sensor such as strain gauge for detecting thenumber of peristaltic contractions that capsule 20 is being subject towithin a particular location in the intestinal tract (in suchembodiments capsule 20 is desirably sized to be gripped by the smallintestine during a peristaltic contraction). Different locations withinthe GI tract have different number of peristaltic contractions. Thesmall intestine has between 12 to 9 contractions per minute with thefrequency decreasing down the length of the intestine. Thus, accordingto one or more embodiments, detection of the number of peristalticcontractions can be used to not only determine if capsule 20 is in thesmall intestine, but the relative location within the intestine as well.In use, these and related embodiments allow for release of medication100 at a particular location in the small intestine.

As an alternative or supplement to internally activated drug delivery(e.g., using a release element and/or sensor), in some embodiments, theuser may externally activate the actuating mechanism 60 to delivermedication 100 by means of RF, magnetic or other wireless signalingmeans known in the art. In these and related embodiments, the user canuse a handheld communication device 13 (e.g., a hand held RF device suchas a cell phone) as is shown in the embodiment of FIG. 1b , to send areceive signals 17 from device 10. In such embodiments, swallowabledevice may include a transmitter 28 such as an RF transceiver chip orother like communication device/circuitry. Handheld device 13 may notonly includes signaling means, but also means for informing the userwhen device 10 is in the small intestine or other location in the GItract. The later embodiment can be implemented through the use of logicresources 29 (e.g., a processor 29) coupled to transmitter 28 to signalto detect and singe to the user when the device is in the smallintestine or other location (e.g., by signaling an input from thesensor). Logic resources 29 may include a controller 29 c (either inhardware or software) to control one or more aspects of the process. Thesame handheld device can also be configured to alert the user whenactuating mechanism 60 has been activated and the selected medication100 delivered (e.g., using processor 29 and transmitter 28). In thisway, the user is provided confirmation that medication 100 has beendelivered. This allows the user to take other appropriatedrugs/therapeutic agents as well as make other related decisions (e.g.,for diabetics to eat a meal or not and what foods should be eaten). Thehandheld device can also be configured to send a signal to swallowabledevice 10 to over-ride actuating mechanism 60 and so prevent delay oraccelerate the delivery of medication 100. In use, such embodimentsallow the user to intervene to prevent, delay or accelerate the deliveryof medication, based upon other symptoms and/or patient actions (e.g.,eating a meal, deciding to go to sleep, exercise etc). The user may alsoexternally activate actuating mechanism 60 at a selected time periodafter swallowing the capsule. The time period can be correlated to atypical transit time or range of transit times for food moving throughthe user's GI tract to a particular location in the tract such as thesmall intestine.

In particular embodiments, the capsule 20 can include seams 22 ofbiodegradable material which controllably degrade to produce capsulepieces 23 of a selectable size and shape to facilitate passage throughthe GI tract as is shown in the embodiment of FIGS. 10a and 10b . Seams22 can also include pores or other openings 22 p for ingress of fluidsinto the seam to accelerate biodegradation as is shown in the embodimentof FIG. 10. Other means for accelerating biodegradation of seams 22 caninclude pre-stressing the seam and/or including perforations 22 f in theseam as is also shown in the embodiment of FIG. 10. In still otherembodiments, seam 22 can be constructed of materials and/or have astructure which is readily degraded by absorption of ultrasound energy,e.g. high frequency ultrasound (HIFU), allowing the capsule to bedegraded into smaller pieces using externally or endoscopically (orother minimally invasive method) administered ultrasound.

Suitable materials for seams 22 can include one or more biodegradablematerials described herein such as PGLA, glycolic acid etc. Seams 22 canbe attached to capsule body 20 using various joining methods known inthe polymer arts such as molding, hot melt junctions, etc. Additionallyfor embodiments of capsule 20 which are also fabricated frombiodegradable materials, faster biodegradation of seam 22 can beachieved by one or more of the following: i) fabricating the seam from afaster biodegrading material, ii) pre-stressing the seam, or iii)perforating the seam. The concept of using biodegradable seams 22 toproduce controlled degradation of a swallowable device in the GI tractcan also be applied to other swallowable devices such as swallowablecameras (or other swallowable imaging device) to facilitate passagethrough the GI tract and reduce the likelihood of such a device becomingstuck in the GI tract. Accordingly, embodiments of biodegradable seam 22can be adapted for swallowable imaging and other swallowable devices.

Another aspect of the invention provides methods for the delivery ofdrugs and other therapeutic agents (in the form of medication 100) intothe walls of the GI tract using one or more embodiments of swallowabledrug delivery device 10. An exemplary embodiment of such a method willnow be described. The described embodiment of drug delivery occurs inthe small intestine SI. However, it should be appreciated that this isexemplary and that embodiments of the invention can be used fordelivering drug in a number of locations in the GI tract including thestomach and the large intestine. For ease of discussion, the swallowabledrug delivery device 10 will sometimes be referred to herein as acapsule. As described above, in various embodiments device 10 may bepackaged as a kit 11 within sealed packaging 12 that includes device 10and a set of instructions for use 15. If the patient is using a handhelddevice 13, the patient may instructed to enter data into device 13either manually or via a bar code 18 (or other identifying indicia 18)located on the instructions 15 or packaging 12. If a bar code is used,the patient would scan the bar code using a bar code reader 19 on device13. After opening packaging 12, reading the instructions 15 and enteringany required data, the patient swallows an embodiment of the swallowabledrug delivery device 10. Depending upon the drug, the patient may takethe device 10 in conjunction with a meal (before, during or after) or aphysiological measurement. Capsule 20 is sized to pass through the GItract and travels through the patient's stomach S and into the smallintestine SI through peristaltic action as is shown in the embodiment ofFIG. 11. Once in the small intestine, the release element 70 is degradedby the basic pH in the small intestine (or other chemical or physicalcondition unique to the small intestine) so as to actuate the actuatingmechanism 60 and deliver medication 100 into the wall of the smallintestine SI according to one or more embodiments of the invention. Forembodiments including a hollow needle or other hollow tissue penetratingmember 40, medication delivery is effectuated by using the actuatingmechanism 60 to advance the needle 40 a selected distance into themucosa of the intestinal wall IW, and then the medication is injectedthrough the needle lumen 40 by advancement of the delivery member 50.The delivery member 50 is withdrawn and the needle 40 is then withdrawnback within the body of the capsule (e.g. by recoil of the spring)detaching from the intestinal wall. For embodiments of device 10 havingmultiple needles, a second or third needle 42, 43 can also be used todeliver additional doses of the same drug or separate drugs 101. Needleadvancement can be done substantially simultaneously or in sequence. Inpreferred embodiments that use multiple needles, needle advancement canbe done substantially simultaneously so as to anchor device 10 in thesmall intestine during drug delivery.

After medication delivery, device 10 then passes through the intestinaltract including the large intestine LI and is ultimately excreted. Forembodiments of the capsule 20 having biodegradable seams 22 or otherbiodegradable portions, the capsule is degraded in the intestinal tractinto smaller pieces to facilitate passage through and excretion from theintestinal tract as is shown in the embodiments of FIGS. 9a and 9b . Inparticular embodiments having biodegradable tissue penetratingneedles/members 40, should the needle get stuck in the intestinal wall,the needle biodegrades releasing the capsule 20 from the wall.

For embodiments of device 10 including a sensor 67, actuation ofmechanism 60 can be effectuated by the sensor sending a signal toactuating mechanism 60 and/or a processor 29/controller 29 c coupled tothe actuating mechanism. For embodiments of device 10 including externalactuation capability, the user may externally activate actuatingmechanism 60 at a selected time period after swallowing the capsule. Thetime period can be correlated to a typical transit time or range oftransit times for food moving through the user's GI tract to aparticular location in the tract such as the small intestine.

One or more embodiments of the above methods can be used for thedelivery of preparations 100 containing therapeutically effectiveamounts of a variety of drugs and other therapeutic agents 101 to treata variety of diseases and conditions. These include a number of largemolecule peptides and proteins which would otherwise require injectiondue to chemical breakdown in the stomach. The dosage of the particulardrug can be titrated for the patient's weight, age or other parameter.Also the dose of drug 101 to achieve a desired or therapeutic effect(e.g., insulin for blood glucose regulation) when delivered by one ormore embodiments of the invention can be less than the amount requiredshould the drug have been delivered by conventional oral delivery (e.g.,a swallowable pill that is digested in the stomach and absorbed throughthe wall of the small intestine). This is due to the fact that there isno degradation of the drug by acid and other digestive fluids in thestomach and the fact that all, as opposed to only a portion of the drugis delivered into the wall of the small intestine and/or peritoneal wall(or other lumen in the intestinal tract, e.g., large intestine, stomach,etc.). Depending upon the drug 101, the dose 102 delivered inpreparation 100 can be in the range from 100 to 5% of a dose deliveredby conventional oral delivery (e.g., a pill) to achieve a desiredtherapeutic effect (e.g., blood glucose regulation, seizure regulation,etc.) with even lower amounts contemplated. The particular dosereduction can be titrated based upon the particular drug, the amount ofdegradation occurring in the GI tract for conventional oral methods, thefrequency of dosing vs dosing using embodiments of the swallowablecapsule described herein, the condition to be treated, and the patient'sweight, age and condition. For some drugs (with known levels ofdegradation in the intestinal tract) a standard dose reduction can beemployed (e.g., 10 to 20%). Larger amounts of dose reduction can be usedfor drugs which are more prone to degradation and poor absorption. Inthis way, the potential toxicity and other side effects (e.g., gastriccramping, irritable bowel, hemorrhage, etc.) of a particular drug ordrugs delivered by device 10 can be reduced because the ingested dose islowered. This in turn, improves patient compliance because the patienthas reduction both in the severity and incidence of side effects.Additional benefits of embodiments employing dose reduction of drug 101include a reduced likelihood for the patient to develop a tolerance tothe drug (requiring higher doses) and, in the case of antibiotics, forthe patient to develop resistant strains of bacteria. Also, other levelsof dose reduction can be achieved for patients undergoing gastric bypassoperations and other procedures in which sections of the small intestinehave been removed or its working (e.g., digestive) length effectivelyshortened.

In addition to delivery of a single drug, embodiments of swallowabledrug delivery device 10 and methods of their use can be used to delivera plurality of drugs for the treatment of multiple conditions or for thetreatment of a particular condition (e.g., protease inhibitors fortreatment HIV AIDS). In use, such embodiments allow a patient to forgothe necessity of having to take multiple medications for a particularcondition or conditions. Also, they provide a means for facilitatingthat a regimen of two or more drugs is delivered and absorbed into thesmall intestine and thus, the blood stream, at about the same time. Dueto difference in chemical makeup, molecular weight, etc., drugs can beabsorbed through the intestinal wall at different rates, resulting indifferent pharmacokinetic distribution curves. Embodiments of theinvention address this issue by injecting the desired drug mixtures atsubstantially the same time. This in turn, improves the pharmacokineticsand thus the efficacy of the selected mixture of drugs. Additionally,eliminating the need to take multiple drugs is particularly beneficialto patients who have one or more long term chronic conditions includingthose who have impaired cognitive or physical abilities.

In various applications, embodiments of the above methods can be used todeliver preparations 100 including drugs and therapeutic agents 101 toprovide treatment for a number of medical conditions and diseases. Themedical conditions and diseases which can be treated with embodiments ofthe invention can include without limitation: cancer, hormonalconditions (e.g., hypo/hyper thyroid, growth hormone conditions),osteoporosis, high blood pressure, elevated cholesterol andtriglyceride, diabetes and other glucose regulation disorders, infection(local or systemic, e.g., septicemia), epilepsy and other seizuredisorders, osteoporosis, coronary arrhythmia's (both atrial andventricular), coronary ischemia anemia or other like condition. Stillother conditions and diseases are also contemplated.

In many embodiments, the treatment of the particular disease orcondition can be performed without the need for injecting the antibodyor other therapeutic agent (or other non-oral form of delivery such assuppositories) but instead, relying solely on the therapeutic agent(s)that is delivered into the wall of the small intestine and/or peritonealwall or other portion of the GI tract. Similarly, the patient need nottake conventional oral forms of a drug or other therapeutic agent, butagain can rely solely on delivery into the wall of the small intestineand/or peritoneal wall using embodiments of the swallowable capsule. Inother embodiments, the therapeutic agent(s) delivered into the wall ofthe small intestine and/or peritoneal wall can be delivered inconjunction with an injected dose of the agent(s). For example, thepatient may take a daily dose of therapeutic agent using the embodimentsof the swallowable capsule, but only need take an injected dose everyseveral days or when the patient's condition requires it (e.g.,hyperglycemia). The same is true for therapeutic agents that aretraditionally delivered in oral form (e.g., the patient can take theswallowable capsule and take the conventional oral form of the agent asneeded). The dosages delivered in such embodiments (e.g., the swallowedand injected dose) can be titrated as needed (e.g., using standard doseresponse curve and other pharmacokinetic methods can be used todetermine the appropriate dosages). Also, for embodiments usingtherapeutic agents that can be delivered by conventional oral means, thedose delivered using embodiments of the swallowable capsule can betitrated below the dosage normally given for oral delivery of the agentsince there is little or no degradation of the agent within the stomachor other portion of the intestinal tract (herein again standard doseresponse curve and other pharmacokinetic methods can be applied).

Various embodiments of preparation 100 containing one or more drugs orother therapeutic agents 101 for the treatment of various diseases andconditions will now be described with references to dosages. It shouldbe appreciated that these embodiments, including the particulartherapeutic agents and the respective dosages are exemplary and thepreparation 100 can comprise a number of other therapeutic agentsdescribed herein (as well as those known in the art) that are configuredfor delivery into a luminal wall in the intestinal tract (e.g., thesmall intestinal wall) using various embodiments of device 10. Thedosages can be larger or smaller than those described and can beadjusted using one or more methods described herein or known in the art.

In a group of embodiments, therapeutic agent preparation 100 cancomprise a therapeutically effective dose of growth hormone for thetreatment of one or more growth disorders, as well as wound healing. Inone embodiment, preparation 100 can contain a therapeutically effectiveamount of growth hormone in the range of about 0.1-4 mg, with particularranges of 0.1-1, 1-4, 1-2, and 2-4 mg, with still larger rangescontemplated. The particular dose can be titrated based on one or moreof the following factors: i) the particular condition to be treated andits severity (e.g. level and particular type of hypercholesterolemia ordyslipidemia); ii) the patient's weight; iii) the patient's age; and iv)the frequency of dosage (e.g. daily vs. twice daily).

Drug delivery compositions and components of known drug delivery systemsmay be employed and/or modified for use in some embodiments of theinventions described herein. For example, micro-needles and othermicrostructures used for delivery of drugs through the skin surface withdrug patches may be modified and included within the capsules describedherein and used to instead deliver a drug preparation into a lumen wallof the gastrointestinal tract such as the of the small intestine and/orperitoneal wall. Suitable polymer micro-needle structures may becommercially available from Corium of California, such as the MicroCor™micro delivery system technology. Other components of the MicroCor™patch delivery systems, including drug formulations or components, mayalso be incorporated into the capsules described herein. Alternatively,a variety of providers are commercially available to formulatecombinations of polymers or other drug-delivery matrices with selecteddrugs and other drug preparation components so as to produce desiredshapes (such as the releasable tissue-penetrating shapes describedherein) having desirable drug release characteristics. Such providersmay, for example, include Corium, SurModics of Minnesota, BioSensorsInternational of Singapore, or the like.

One advantage and feature of various embodiments of the therapeuticcompositions described herein is that by being enclosed or otherwisecontained in the swallowable capsule or other swallowable device, theantibody (e.g. an AP-antibody such as Alirocumab) or other biologic(e.g. peptide or protein) drug payload is protected from degradation andhydrolysis by the action of peptidases and proteases in thegastrointestinal (GI) tract. These enzymes are ubiquitous throughoutliving systems. The GI tract is especially rich in proteases whosefunction is to break down the complex proteins and peptides in one'sdiet into smaller segments and release amino acids which are thenabsorbed from the intestine. The devices and compositions describedherein are designed to protect the therapeutic peptide, antibody orother protein from the actions of these GI proteases and to deliver thepeptide or protein payload directly into the wall of the intestine.There are two features in various embodiments of the compositionsdescribed herein which serve to protect the protein or peptide payloadfrom the actions of GI proteases. First, in certain embodiments, thecapsule shell, which contains the deployment engine and machinery, doesnot dissolve until it reaches the duodenal and sub-duodenal intestinalsegments, owing to the pH-sensitive coating on the outer surface of thecapsule which prevents its dissolution in the low pH of the stomach.Second, in certain embodiments, hollow polymer micro-spears (e.g.,polyethylene oxide, maltose, silicone etc.) contain the actualtherapeutic peptide or protein; the polymer micro-spears are designed topenetrate the intestine muscle as soon as the outer capsule shelldissolves; and the micro-spears themselves slowly dissolve in theintestinal muscle wall to release the drug payload. Thus, the peptide,antibody protein payload is not exposed to the actions of the GIproteases and therefore does not undergo degradation via proteolysis inthe GI tract. This in turn, contributes to the high bioavailability ofthe therapeutic peptide or protein versus what would be expected if oneor both of the above approaches were not used and the peptide or proteinwere exposed to the GI proteases. In particular for embodiments of thecompositions comprising antibodies, such approaches preserve the bindingaffinity and specificity of the antibody allowing it to bind to thetarget antigen (e.g. one or more members of the PCSK9 family ofcytokines)

Anti-PCSK9 Antibodies

As discussed above, various embodiments of the invention providetherapeutic compositions comprising antibodies or other binding proteinswhich attenuate the biological effects of PCSK9 and its analogues andderivatives by either binding to the PCSK9 molecule or it receptors forthat PCSK9 so as to prevent in either case the PCSK9 from attaching tothe receptor for that PCSK9.

A brief explanation will now be presented on PCSK9 molecules. Thismolecule is a serine protease encoded by a gene comprising 12 exons,located on chromosome 1p32.3. It is synthesized primarily by the liverand intestine as a 692-amino acid precursor (˜75 kDa) in which a signalpeptide (residues 1-30) and a prodomain (residues 31-152) precede acatalytic domain (residues 153-451) that contains the canonical N-H-Scatalytic triad, followed by a C-terminal domain (residues 452-692).Pro-PCSK9 undergoes autocatalytic intramolecular processing between theQ152 and S153 residues in the endoplasmic reticulum to form a matureenzyme (˜62 kDa). The cleavage of the prodomain is required for PCSK9maturation and secretion. This was demonstrated by experiments where theprodomain and the catalytically inactive 62 kDa PCSK9 moiety wereco-expressed, allowing the exit of a non-covalently boundPCSK9/prodomain complex from the endoplasmic reticulum to the Golgicomplex, which ultimately promoted LDLR degradation. It is noteworthythat a naturally occurring amino acid substitution within the PCSK9cleavage site (Q152H) has recently been described in a paper by Mayne J.T, et al (Novel loss-of-function PCSK9 variant is associated with lowplasma LDL cholesterol in a French-Canadian family and with impairedprocessing and secretion in cell culture. 2011 Clin. Chem. 57:1415-1423) which is fully incorporated herein for all purposes. Thismutation prevents autocatalytic processing, thereby precluding PCSK9secretion, and is associated with a 48% reduction in plasma LDL-Clevels. After cleavage, the prodomain forms hydrogen bonds with keyamino acids of the catalytic domain, thereby preventing access of otherpotential substrates to the catalytic pocket of PCSK9. The ability ofPCSK9 to promote LDLR degradation is, therefore, independent of itscatalytic activity, indicating that PCSK9 functions as a chaperone, amode of action that is unique among serine proteases. PCSK9 undergoesself-assembly and forms PCSK9 dimers or trimers which have greater LDLRdegrading activity. One of the gain-of-function (GOF) mutations of PCSK9(D374Y) is characterized by an enhanced PCSK9 self-assembly. The mainroute of PCSK9 elimination is through LDLR binding, althoughLDLR-independent mechanisms of PCSK9 clearance must exist. Up to 30% ofPCSK9 is bound to LDL-C in mice and normal lipidemic subjects. In mice,PCSK9 is also bound to high-density lipoprotein (HDL). The aminoresidues 31-52 of the prodomain are required for the binding of PCSK9 toLDL-C.

According to various embodiments, such anti-PCSK9 antibodies, hereinAP-antibodies, may correspond to a full-length antibody or anantigen-binding portion thereof. Also, they will typically, though notnecessarily, comprise monoclonal antibodies which are human or humanizedantibodies using methods known in the art. As used herein, the term“antibody”, refers to any immunoglobulin (Ig) molecule comprised of fourpolypeptide chains, two heavy (H) chains and two light (L) chains, orany functional fragment, mutant, variant, or derivation thereof, whichretains the essential epitope binding features of an Ig molecule. Also,as used herein, “epitope” means a segment or feature of a proteincapable of specific binding to an antibody. Also, as used herein, an“anti-PCSK9 antibody (AP-antibody),” “AP-antibody portion,” or“AP-antibody fragment” and/or “AP-antibody variant” and the like includeany protein or peptide containing molecule that comprises at least aportion of an immunoglobulin molecule, including, but not limited to atleast one complementarity determining region (CDR) of a heavy or lightchain or a ligand binding portion thereof, a heavy chain or light chainvariable region, a heavy chain or light chain constant region, aframework region, or any portion thereof, or at least one portion of aPCSK9 receptor or binding protein, which can be incorporated into anantibody of the present invention. Such AP-antibodies optionally furtheraffect a specific ligand, such as but not limited to where such anantibody modulates, decreases, increases, antagonizes, agonizes,mitigates, alleviates, blocks, inhibits, abrogates and/or interfereswith PCSK9 activity or binding, or with PCSK receptor activity orbinding, in vitro, in situ and/or in vivo. According to one or moreembodiments, the PCSK9 antibodies may correspond to one or more ofAlirocumab (available from Regeneron/Sanofi), Evolocumab (from Amgen),or Bococizumab (from Pfizer).

AP-antibodies or other binding protein provided by embodiments of theinvention are particularly useful for treating hypercholesterolemia andother related conditions such as dyslipidemia and various forms ofcardiovascular disease including arteriolosclerosis and/or coronary,cerebral and peripheral vascular stenosis and related conditions.Specific forms of hypercholesterolemia which can be treated includedwithout limitation heterozygous familial hypercholesterolemia, andhomozygous familial hypercholesterolemia. Such embodiments result in thedelivery of AP-antibody with particular pharmacokinetic properties whichare advantageous verses intravenous, sub-dermal or intramuscularinjection. They also allow for the usage of dosages which provide one ormore of the following benefits including higher therapeutic ratio,reduced incidence of allergic reaction (including e.g., anaphylacticshock; myalgia and neurocognitive and ophthalmologic events, the lattertwo observed during clinical trials of Alirocumab) and reducedimmunogenicity and/or immunogenic reaction (verses subcutaneous and/orintramuscular injection). In one embodiment, the reduced incidence ofallergic reaction can be determined by comparison of such incidences forpatient populations who are delivered drug by standard injection (e.g.,intramuscular, intravenous etc.) vs the oral delivery for traditionalcompounds and then using that reduction to model a predicted reductionfor known incidences of allergic reaction in patient populations for oneor more of the AP antibodies described herein (e.g., Alirocumab,Evolocumab, Bococizumab) etc.

Dosage

According to one or more embodiments, the dosage of AP-antibodyadministered using one or more embodiments of the swallowable capsule isusually, though not necessarily, a therapeutically effective amount. Asused herein, the phrase “therapeutically effective amount” means a doseof anti-AP antibody that results in: i) a detectable improvement in oneor more clinical measurements (e.g. serum cholesterol and/or lipidlevels) and/or symptoms of hypercholesterolemia and/or dyslipidemia in apatient; or ii) a dose of AP-antibody that inhibits, prevents, lessens,or delays the progression of hypercholesterolemia and/or dyslipidemia ina patient e.g., such as i) the development of arteriosclerosis; ii)coronary stenosis and/or ischemia; or iii) peripheral artery stenosis orischemia. According to various embodiments, a therapeutically effectiveamount of AP-antibody delivered by embodiments of the invention can bein a range from about 0.05 mg to about 200 mg, with specific embodimentsof about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0mg, about 5 mg, about 7, about 10 mg, about 11 mg, about 12 mg, about 15mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg,about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about170 mg, about 180 mg, about 190 mg, about 200 mg, of the anti-PCSK9antibody.

Embodiments of PCSK9 Neutrializing Proteins Comprising Alirocumab,Evolocumab or Bococizumab

In one or more embodiments, the AP-antibodies may correspond to one ormore of Alirocumab, Evolocumab or Bococizumab and their analogue andderivatives. Alirocumab is a fully human monoclonal antibody to PCSK9.It binds to and inhibits and/or neutralizes the activity of PCSK9 whichas described above has been implicated in lowering the LDL-cholesterolor hyperlipidemia, a risk factor for the development of atherosclerosisand associated ischemic cardiovascular disease (CVD), such as myocardialinfarction and stroke. Positive results from clinical study werepublished and won a priority review by the FDA.

From its use as a monotherapy during clinical trials, Alirocumab hasbeen shown to reduce LDL-C as much as intensive statin treatment and inconjunction with statin, Alirocumab significantly enhanced reduction ofserum levels of LDL-C. For example, among patients with baselineLDL-C≥100 mg/dL on atorvastatin 10 mg daily, an increase in atorvastatinto 80 mg daily resulted in a further 17% decrease in LDL-C, whereas anincrease in atorvastatin to 80 mg daily along with Alirocumab 150 mgevery 2 weeks resulted in a further 73% decrease. The Alirocumab group,as compared with the placebo group, had higher rates of injection-sitereactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitiveevents (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%). In apost hoc analysis, the rate of major adverse cardiovascular events(death from coronary heart disease, nonfatal myocardial infarction,fatal or nonfatal ischemic stroke, or unstable angina requiringhospitalization) was lower with Alirocumab than with placebo (1.7% vs.3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominalP=0.02). (ODYSSEY LONG TERM ClinicalTrials.gov number, NCT01507831).

The doses of Alirocumab for such treatment can be delivered usingvarious embodiments of the swallowable devices including swallowablecapsules (described herein) and can be in a range from about 1 to 50 mgper day, with specific embodiments of about 5, 10, 20, 25, 30 and 40 mgper day. In preferred embodiments for the treatment of hyperlipidemia,the dose of Alirocumab delivered using embodiments of the swallowablecapsule can be in a range of about 5 to 11 mg per day, with specificembodiments of 5, 5.5, 6, 7, 8, 9, 10.0, 10.5 and 10.7 mg per day forvarious forms of hypercholesterolemia and/or dyslipidemia. Similardosages may be used for embodiments for delivering AP-antibodiescorresponding to one or both of Evolocumab or Bococizumab or theiranalogues and derivatives. In particular embodiments using Evolocumab,doses of 5, 6, 7, 8, 9 and 9.3 mg can be delivered per day for variousforms of hypercholesterolemia and/or dyslipidemia and 14 mg per day forpatients with homozygous familial hypercholesterolemia. In particularembodiments using Bococizumab doses of 7, 8, 9, 10, 10.7 and 11 mg perday can be delivered for treating various forms of hypercholesterolemiaand/or dyslipidemia. These doses can be delivered by means of one ormore swallowable capsules (including multiple capsules taken at the sametime) taken at once or over the course of a day. For these and otherdosages, the daily dose may be initiated after a loading dose which maybe administered via injection (e.g., IV, intramuscular or subdermal) orother delivery method. The dose may be titrated for an individualpatient based on one or more of the patient's, weight, age, severity ofcondition, combination with other drugs, duration of the drug regimin,amount of the loading dose and treatment efficacy index known in the artfor a given condition. For example in the case of Bococizumab, initialdosing can be adjusted to achieve reductions in (LDL-C) of about 40 to60 mg/dl with a specific range of about 50 to 54 mg/dl in serumlow-density lipoprotein cholesterol. Correspondingly doses of of theselected AP-antibody (e.g. Alirocumab, Evolocumab or Bococizumab) can bedelivered to reduce percent amount of LDL-C or serum lipids in a rangefrom about 10 to 80%, with specific embodiments of 20, 30, 40, 46, 50,60, or 70. After a desired reduction in in LDL-C or lipids has beenachieved, then the dosage of the delivered antibody can then bedecreased or otherwise titrated accordingly. For example dosages of theAP-antibody can then be reduced once LDL-C levels in patients have beendecreased to ≤25 mg/dl. Also in related embodiments, once some level ofLDL-C levels reduction has been achieved dosages can be redured fromabout 32 to about 35% % after 8 to 10 weeks of delivery.

Embodiments of Combination Therapies for LDL-C Reduction Using PCSK9Neutrializing Proteins.

In alternative or additional embodiments for reducing LDL-C levels in apatient, the oral delivery of PCSK9 neutrializing proteins (e.g., usingembodiments of the swallowable capsule) may be combined with othertherapies for achieving such a reduction including the use of variousorally delivered agents for reducing LDL-C levels. The orally delivereddose of the LDC-reducing agent may given selected time before,concurrently or after the patient takes an oral dose of PCSK9neutrializing proteins (e.g, a PN-antibody such as Alirocumab) usingembodiments of the swallowable capsule. In many embodiments the orallydelivered LDL-C reducing agents may correspond to one or more statins.In particular embodiments the statin may correspond to atorvastatin andits analogues. For example, according to one or or embodiments an orallydelivered dose of atorvastatin may taken before, during or after thepatient takes a swallowable dose of a PN-antibody, such as Alirocumab,Evolocumab or Bococizumab. The dose of the atorvastatin may be in therange of about 10 mg to 80 mg daily. In use such combination therapiessuch as the oral delivery of Alirocumab and atorvastatin can provide foradditional levels of LDL-C levels reduction than possible withindividual administration of each medication alone. For example, for anapproximate 80 mg daily oral dosage of atorvastatin combined with anapproximate 10.7 mg daily dosage of Alirocumab additional decreases inLDL-C levels of up to 73% may be achieved. According to variousembodiments, the dose of orally delivered PN-antibody and other LDL-Creducing agent (e.g atorvastatin) may adjusted relative to one another(depending on various factors, e.g the pateints initial LDC-levels,weight, age, etc) to optimize or otherwise achieve a selected level ofLDL-C reduction in the patent. Further the dose of the two LDL-Creducing agents and their times of delivery can be adjusted so as toachieve a synergistic effect in LDL-C reduction. According, to one ormore embodiments, the doses of each agent for producing such asynergistic effect and/or LDC-C reduction optimization can be determinedby using known dose responsive curves for each medication and then usingpharmacodynamic and/or pharmacokinetic models to predict the dose whichproduces the optimal levels of LDC-C reduction. Such models maycorrespond to one or more of exponential, first order, second order,differential equation or other model known in the pharmaceutical orbiochemical art. The models may also correspond to various networkmodels known in the pharmaceutical and biological arts including, forexample, protein-protein interaction networks (or PPI network which arebased on intentional physical or functional associations betweenproteins) such as that described by D Chen, et al in Systematic SynergyModeling: Understanding Drug Synergy From A Systems Biology Perspective,BMC Syst Biol. 2015; 9: 56 which is incorporated by reference herein forall purposes. Another example of a suitable network model includes anenhanced Petri-Net (EPN) model such as that described by G. Jin et al inAn Enhanced Petri-Net Model To Predict Synergistic Effects Of PairwiseDrug Combinations From Gene Microarray Data. Bioinformatics Volume 27,Issue 13 P 310-316 which is also incorporated by reference herein forall purposes. In still another approach, dose response curves usingcombinations of AP-antibody and other LDL-C reducing agent can then bedeveloped and used with with one or more of the aforementioned models topredict dosages for optimizing an LDL-C reducing effect.

Alternative Embodiments of PCSK9 Neutrializing Proteins.

Other embodiments of the invention contemplate the oral delivery ofother PCSK9 neutrializing proteins and or polypeptides which maycorrespond to one or more of adnectins, memetic peptides, small moleculeinhibitors, antisense oligonucleotides, and RNA interence (RNA-i)compounds. Suitable adnectins include BMS-962476. Suitable mimeticpeptides include EGF-AB peptide fragment, LDLR Sub-fragment and LDLR DNAconstructs. Suitable small molecule inhibitors include SX-PCK9. Suitableantisense oligonucleotides include ISIS394814 and SPC 4061. SuitableRNA-I compounds include ALN-PCS02. Further description of these andother PCSK9 neutrializing proteins including specific molecules, theirproperties, dosages and sources may be found in the table shown in FIG.21.

Benefits of Delivery of AP-Antibodies into the Intestinal Wall or OtherLocation in the Intestinal Tract.

In use, embodiments of the invention providing for delivery of anAP-antibody or PN-protein into wall of the intestine and/or peritonealwall and adjoining tissue (e.g the peritinoeam) or other target site inthe intestinal tract e.g the larger intestine) for treatment of one ormore of the above or conditions provide a number of benefits overinjected forms AP-antibodies such as Alirocumab, Evolocumab andBococizumab. Such benefits can include without limitation: i) a highertherapeutic ratio; ii) reduced incidence and severity of the adversereactions including one or more of: anaphylactic shock or other allergicreaction (including at the injection site), bruising at the injectionsite, nasopharyngitis, upper respiratory tract infections, influenza,back pain myalgia, neurocognitive events, and ophthalmologic events; anddecreased immunogenicity and/or immunogenetics reaction. In the latercase, such immunogenic reactions can result in the development in thepatient of antibodies to the AP antibodies themselves resulting inreduced efficacy resulting in the requirement of higher doses of drugand/or an unwanted immune response. These benefits are due to one ormore of the following i) the much smaller doses of AP-antibodies or (orother AP-antibody or PN-protein) that are delivered by embodiments ofthe invention; ii) doses are delivered daily vs weekly or monthly; andiii) the fact that doses are delivered orally vs intravasccularly.

In many embodiments, the therapeutic ratio of dosages of AP-antibodiesdelivered orally by embodiments of the invention can be increasedsignificantly over that for AP-antibody(s) delivered by injection (e.g.,intravenously, intramuscularly, or subcutaneously, etc on a weekly,biweekly, or monthly basis). In various embodiments, the term“significantly” corresponds to an increase in the therapeutic ration inan amount of two times or greater, e.g, seven to thirty times greater ormore. For AP-antibodies or (or other AP-antibody or PN-protein) that aretypically delivered in weekly doses when injected (e.g intravenously,intramuscularly, or subcutaneously, etc), the therapeutic ratio (e.gToxic Dose/Effective Dose) can be increased by a factor of seven whendelivered in daily oral doses using the swallowable devices provided bythe invention, while in the case of monthly injected doses of APantibodies the therapeutic ration can be increased by a factor of 30when delivered daily oral doses by embodiments of the invention.Further, increases can be obtained when the oral dose of AP-antibody isgiven multiple times over a day. Similar improvements (e.g by a factorof 7, 30 or even more) can be seen in the incidence in one or more ofimmunogenicity/immune response (vs intramuscular and/or subcutaneousinjection), allegeric reaction, and other adverse reactions.Immunogenicity/immune response, being the production by the body ofantibodies to the administered AP-antibody which neutralize or otherwisediminish the clinical efficacy of the AP-antibody. The reduction in theincidence and severity of allergic reaction can be reduced by a factorof two up to 30 due to the fact the antibodies are given in daily dosesvs monthly doses which tends to desensitize the immune system (thedegree of allergic reaction can be determined using methods known in theart and may be correlated to one or more in vitro tests known in theart). Similarly, the degree of reduced immunogenicity and/or immuneresponse can be reduced by a factor of two to as much as thirty or moredue three possible factors: 1) the doses are not deliveredsubcutaneously and/or intramusculary (which tend to exacerbate suchresponses); 2) the doses are delivered in much smaller amounts, e.g by afactor of 7 to as much as 30 depending on whether the injected dose isdelivered weekly, biweekly, monthly etc; and 3) as discussed above thedose of AP-antibody is delivered to the upper portions of the smallintestine avoiding the peyer's patches and subsequent production ofimmune cells and other immune response. The amount of immuneresponse/immunence to a given AP-antibody (e.g., Alirocumab) can bequantified using one more more immunologic analytical methods known inthe art to measure, for example, the production of generated antibodiesto the delivered AP-antibody or other PN-protein and/or the percentageof the administered AP-antibodies that are neutralized by the patientsown antibodies. In these and related embodiments, the dosage and doseregiment of the AP-antibody can configured to yield a minimal immuneresponse in the patient, wherein minimal means less than 10% of thedelivered AP-antibodies are neutralized by the patients own antibodiesand more preferrably less than 5%.

In other embodiments the immune response and/or allergic response to theadministered AP-antibody can be quantified by measuring differences inthe serum titer of antibodies to the AP-antibody when administered indaily oral doses vs biweekly or monthly intravenous doses. In these andrelated embodiments, the dosage and dose regiment of the AP-antibody canconfigured to yield a minimal immune response in the patient, whereinminimal means less than a 10% increase in the serum concentration of thepatient's own antibodies against the administered AP-antibody and morepreferrably less than a 5% increase.

In related approaches, the serum titer of cytokines (e.g interleukins,such as interleukin 7) and/or white blood cells can be measured for eachform of administration. In these and related embodiments, the dosage anddose regiment of the AP-antibody can configured to yield a minimalimmune response in the patient, wherein minimal means less than a 10%increase in the serum concentration of one or more of the patients whiteblood cells and/or a particular cystokine (e.g., interleukin 7) and morepreferrably less than a a 5% increase. In related embodiments, immuneresponse can be quantified by using changes in white blood celldifferentials (e.g increase in the % of Eosinophils or Basophils whichoccur in allergic reactions). In these and related embodiments, thedosage and dose regiment of the AP-antibody can configured to yield aminimal immune response in the patient, wherein minimal means less thana 10% change in the percentage of a particular type of white blood cell(e.g., Eosinophils) in the patient's total white blood cell count.

Another benefit achieved by delivering doses of various AP-antibodies orother PN-protein in daily doses versus biweekly or monthly doses byconventional injection means (e.g. by intravenous, intramuscular orsubcutaneous injection) is a reduction in the fluctuation of thepatients plasma concentration profile for the particular antibody whichin turn results in a much smoother plasma concentration profile. Using apharmacokinetic model explained in more detail in Appendix 1, plasmaconcentration curves were generated for the delivery of Alirocumab(FIGS. 22a and 22b ) in biweekly delivery periods verses daily doses(which were titrated down from biweekly dose). As can be seen from thefigures, the amount of daily fluctuation in the curves is much less forAlirocumab. Also a value known as “% steady state fluctuation” wascalculated for each of these antibodies using an equation shown anddescribed in detail in Appendix 2. The value reflects the amount ofdaily fluctuation in the plasma concentration of a given drug. As shownin Table 1 below, the amount of steady state fluctuation in plasmaconcentration of the particular antibody was reduced significantly whenthe antibody was delivered by embodiments of the invention in dailydoses vs subcutaneous injection (66.3% to 0.39%). With the result beingabout a 170 times reduction in steady state fluctuation for Alirocumab.The model has also been used to show reductions in steady plasmafluctuations for two anti-interleukin antibodies: Secukinumab andBrodalumab (as is described in U.S. patent application Ser. No.15/150,379) with results shown in Table 2. In these cases, thereductions in steady fluctuation were from 171 to 216x. Thus, the modelconsistently show reductions of 170 to 216% in the steady plasmaconcentrations of a given drug (e.g. AP-antibody) when the drugs isgiven in daily doses using embodiments of the invention vs biweekly ormonthly using subcutaneous injections. Using such a model, similarabsolute values (e.g., 0.12 to 0.39%) and reductions are expected forEvolocumab or Bococizumab in % steady state fluctuation. The benefits ofsuch reductions include one more of the following: reduced risk ofadverse event, reduced allergic reaction and immunogenicity; as welllonger period of time when the patient is kept in the therapeutic index(range) for a given antibody allowing the antibody to better and moreconsistently treat the intended condition. The reduced steady statefluctuation may also be used to quantify a reduction in the patient'simmune response to a particular AP-antibody. Such a reduction may beproportional (e.g. directly proportional, fractionally proportion, etc.)or in the form of first order or second order proportionality.

TABLE 1 % Steady State Fluctuation in Plasma/Serum Concentration ofAlirocumab using conventional subcutaneous dosing of the drug vs dailydosing by embodiments of the invention. Alirocumab Conventional 66.33%Subcutaneous dosing Daily Dosing via  0.39% Embodiments of the inventionDecrease in Steady 170x Fluctuation

TABLE 2 % Steady State Fluctuation in Plasma/Serum Concentration ofSecukinumab and Brodalumab using conventional subcutaneous dosing of thedrug vs daily dosing by embodiments of the invention. SecukinumabBrodalumab Conventional Subcutaneous dosing 56.15% 20.48% Daily dosingusing embodiments of the  0.26%  0.12% invention Decrease in SteadyFluctuation 216x 171x

Embodiments of Bioequivalents of AP-Antibodies

Embodiments of the invention also contemplate the compositions and useof AP antibodies and antibody fragments which encompass proteins havingamino acid sequences that vary from the AP-antibodies described herein.Such variant AP antibodies and antibody fragments comprise one or moreadditions, deletions, or substitutions of amino acids (e.g. leucine vslysine) when compared to the amino-acid sequence of a parentAP-antibody, but exhibit biological activity that is essentiallyequivalent to that of the described AP antibodies in terms of theability of the variant to bind and/or neutralize a PCSK9 molecule.

Embodiments of Methods of Treating Hypercholesterolemia and/orDyslipidemia Using AP Antibodies Delivered into the Intestinal Wall.

In one or more embodiments, the invention provides methods for treatinghigh cholesterol or other form of hypercholesterolemia and/ordyslipidemia comprising: i) administering a dose of PCSK9 antibody tothe patient using one or more embodiments of the swallowable capsuledescribed herein; ii) monitoring a cholesterol and/or lipid level of thepatient in response to the administered PCSK9; and then iii) titratingthe subsequent doses and/or dosing regiments accordingly. Specific PCSK9antibodies which can be administered to the patient using embodiments ofthe invention may correspond to one or more of Alirocumab, Evolocumab orBococizumab as well as their analogues and derivatives. Specific formsof hypercholesterolemia which can be treated include without limitation,heterozygous familial hypercholesterolemia, and homozygous familialhypercholesterolemia (related conditions such as arteriolosclerosis canalso be treated with such methods). Higher doses of one or AP-antibodiesmay delivered depending upon the particular initial level of cholesteroland/or particular type of hypercholesterolemia. For example, in the caseof homozygous familial hypercholesterolemia larger doses can be given ofthe selected AP-antibody such as Evolocumab. In particular embodiments,a daily dose of around 13 to 15 mg of Evolocumab can be given, with aspecific embodiment of about 14 mg per day. Also doses can be titrateddown once a desired reduction in LDL-C and/or serum lipid levels havebeen achieved. For example according to one or more embodiments, dosagesof the AP antibodies can then be reduced once LDL-C levels in patientshave been decreased to ≤25 mg/dl. The dosages may also be reduced aftera number of weeks of treatment, for example, reductions from about 32 toabout 35% % after 8 to 10 weeks of delivery. In additional orsupplemental embodiments, genetic testing can be performed on thepatient prior to AP-antibody administration to determine one or more ofthe following: i) the most therapeutically effective AP antibody to use(e.g., that producing the greatest reduction in PCSK9 levels, e.g.Alirocumab, Evolocumab, etc.), ii) the type and amount of adversereactions for a given AP-antibody (t e.g., inflammation and degree of);iii the most effective dosage and/or dose frequency for a givenAP-antibody (e.g. vs Alirocumab, Evolocumab etc.). Genetic testing canusing techniques known in the art can be done looking at single orgroups of genes and can also be done to look for the presence of more ofsingle nucleotide polymorphisms (SNP), multiple nucleotide polymorphism(MNP. Further such testing for one of the results listed above can becorrelated to results for similar antibodies to the AP antibodies orantibodies in antibody families to which AP-antibodies belong.

Pharmacokinetic Metrics for Delivery of AP-Antibodies into theIntestinal Wall

Embodiments of the invention delivering AP-antibodies or other PNproteins into the intestinal wall (e.g., the small intestine) alsoprovide benefits with regard to one or more pharmacokinetic metrics.Pharmacokinetic metrics of note in this regard include withoutlimitation, C_(max), the peak plasma concentration of a drug afteradministration; t_(max), the time to reach C_(max); and t_(1/2), thetime required for the plasma concentration of the drug to reach half itsC_(max) value after having reached C_(max). These metrics can bemeasured using standard pharmacokinetic measurement techniques known inthe art. For example, one approach plasma samples may be taken at settime intervals (e.g., one minute, five minutes, ½ hour, 1 hour, etc.)beginning and then after administration of the AP-antibody or othertherapeutic agent either by use of a swallowable device or bynon-vascular injection. The concentration of the drug in plasma can thenbe measured using one or more appropriate analytical methods such asGC-Mass Spec, LC-Mass Spec, HPLC or various ELISA (Enzyme-linkedimmunosorbent assays) which can be adapted for the particular drug. Aconcentration vs. time curve (also herein referred to as a concentrationprofile) can then be developed using the measurements from the plasmasamples. The peak of the concentration curve corresponds to C_(max) andthe time at which this occurs corresponds to t_(max). The time in thecurve where the concentration reaches half its maximum value (i.e.,C_(max)) after having reached C_(max) corresponds to t_(1/2) this valueis also known as the elimination half-life of the drug. The start timefor determination of C_(max) can be based on the time at which theinjection is made for the case on non-vascular injection and the pointin time at which embodiments of the swallowable device advances one ormore tissue penetrating members (containing the drug) into the smallintestine or other location in the GI tract (e.g., the large intestine).In the latter case, this time can determined using one or more meansincluding a remote controlled embodiment of the swallowable device whichdeploys the tissue penetrating members into the intestine wall inresponse to an external control signal (e.g., an RF signal) or for anembodiment of the swallowable device which sends an RF or other signaldetectable outside the body when the tissue penetrating members havebeen deployed. Other means for detection of tissue penetrating memberdeployment into the small intestine are contemplated such as one moremedical imaging modalities including for example, ultrasound orfluoroscopy. In any one of these studies, appropriate animal models canbe used for example, dog, pig, rat etc. in order to model the humanpharmacokinetic response.

Thus, various embodiments provide a therapeutic composition 100 (alsoreferred to herein as a preparation) comprising an AP-antibody or otherPN proteins. The composition is adapted for insertion into an intestinalwall after oral ingestion, wherein upon insertion, the compositionreleases AP-antibody into the bloodstream from the intestinal wall toachieve a C_(max) faster than an extravascularly injected dose ofAP-antibody that is to say, achieving a C_(max) for the inserted form ofAP-antibody in a shorter time period (e.g., a smaller t_(max)) than thatfor a dose of AP-antibody that is injected extravascularly. Note, thatthe dose of AP-antibody in the composition delivered into the intestinalwall and the dose delivered by extravascular injection, may, but neednot, be comparable to achieve these results. In various embodiments, thecomposition is configured to achieve a t_(max) for AP-antibody (e.g., byrelease of AP-antibody into the bloodstream from the intestinal wall,e.g., that of the small intestine) which is about 80%, or 50%, or 30%,or 20%, or 10% of a t_(max) for an extravascularly injected dose ofAP-antibody. Such an extravascularly injected dose of AP-antibody canbe, for example, a subcutaneous injection or an intramuscular injection.In certain embodiments, the C_(max) attained by delivering AP-antibodyby insertion into the intestinal wall is substantially greater, such as5, 10, 20, 30, 40, 50, 60, 70, 80 or even a 100 times greater, than theC_(max) attained when the AP-antibody is delivered orally withoutinsertion into the intestinal wall for example by a pill otherconvention oral form of AP-antibody or related compound. In someembodiments, the AP-antibody (or other PN protein) composition isconfigured to produce a long-term release of AP-antibody which caninclude periods in the range of about 1 to 60 days, with particularembodiments of 6 to 12 hours, 6 to 24 hours, 12 to 24 hours, 12 to 36hours, 1 to 2 days, 1 to 5 days, 1 to 10 days, 1 to 20 days, two days,three days, five days, seven days, ten days, 15 days, 20 days, 30 days,40 days, 45 days 50 days and 60 days. Also, the composition can beconfigured to produce a long-term release of AP-antibody with aselectable t_(1/2). For example, the selectable t_(1/2) may be 6, or 9,or 12, or 15 or 18, 24, 36, 48 and 60 hours.

Any appropriate dose of AP-antibody (or other PN protein) for aparticular patient may be used, depending on factors such as weight,age, condition, other drugs being taken etc. For example, the dose ofAP-antibody or other AN protein administered may range from about 1 to10 mg, with particular ranges of 1-5, 1-4, 2-4, 2-5 and 2-3 mg andindividual doses of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 mg. Whenadministered subcutaneously, AP-antibody typically has a t_(max) in thebloodstream of about 130 hours. Therefore, when administered in atherapeutic AP-antibody composition as described herein, the t_(max) ofthe AP-antibody will be shortened, e.g., to about 80%, or 50%, or 30%,or 20%, or 10% of the t_(max) for AP-antibody when it is subcutaneouslyinjected.

Various embodiments also provide an AP-antibody (or other PN-protein)composition adapted for insertion into an intestinal wall after oralingestion, wherein upon insertion, the composition releases theAP-antibody (or other PN-protein) into the blood stream from theintestinal wall to achieve a t_(1/2) that is greater than a t_(1/2) foran orally ingested dose of AP-antibody (or other PN-protein) that is notinserted into the intestinal wall. For example, the t_(1/2) of the doseinserted into the intestinal wall may be 100 or 50 or 10 or 5 timesgreater than the dose that is not inserted into the intestinal wall.

According to one or more embodiments, the AP-antibody (or otherPN-protein) may be in solid form, such as a solid form compositionconfigured to degrade in the intestinal wall such as the wall of thesmall intestine or the perineal wall. Also, the solid form compositionmay have, for example, a tissue penetrating feature such as a pointedtip. In one or more embodiments, the solid form AP-antibody compositionmay be in the form of a shaft with a pointed tip, such as needle ordart, allowing the composition to be penetrate and be inserted into theintestinal wall or peritoneal wall. The AP-antibody (or otherPN-protein) composition may comprise at least one biodegradable materialand/or may comprise at least one pharmaceutical excipient, including abiodegradable polymer such as PGLA or a sugar such as maltose. In otherembodiments, the AP-antibody (or other PN-protein) may in a semi-solidor liquid form encased or otherwise fabricated into embodiments of thetissue penetrating member.

Various embodiments of the AP-antibody (or other PN-protein) compositiondescribed herein may be adapted to be orally delivered in a swallowablecapsule. In certain embodiments such a swallowable capsule may beadapted to be operably coupled to a mechanism having a firstconfiguration and a second configuration, the AP-antibody (or otherPN-protein) composition being contained within the capsule in the firstconfiguration and advanced out of the capsule and into the intestinalwall in the second configuration. Such an operably coupled mechanism maycomprise at least one of an expandable member, an expandable balloon, avalve, a tissue penetrating member, a valve coupled to an expandableballoon, or a tissue penetrating member coupled to an expandableballoon.

In some embodiments, the AP-antibody (or other PN-protein) may beconfigured to be delivered within a lumen of a tissue penetrating memberand/or the AP-antibody (or other PN-protein) composition may be shapedas a tissue penetrating member advanceable into the intestinal wall. Thetissue penetrating member may be sized to be completely contained withinthe intestinal wall, and/or it may include a tissue penetrating featurefor penetrating the intestinal wall, and/or it may include a retainingfeature for retaining the tissue penetrating member within theintestinal wall. The retaining feature may comprise, for example, abarb. In some embodiments, the tissue penetrating member is configuredto be advanced into the intestinal wall by the application of a force(e.g., a mechanical force) to a surface of the tissue penetratingmember. Desirably, the tissue penetrating member has sufficientstiffness and/or column strength to be advanced completely into theintestinal wall and/or the surface of the penetrating member by theapplication of the mechanical or other force (e.g., electromagnetic,).In various embodiments, the column strength/stiffness of the tissuepenetrating member can range from about 1 to 20 lbs, 7 to 20 lbs, 8 to12 lbs, with individual embodiments of 7, 8, 9, 10 and 11 lbs. Thecolumn strength can be achieved by selection of one or more of thematerial selection and diameter of the tissue penetrating member. Inmany embodiments, the tissue penetrating member is configured to beoperatively coupled to an expandable balloon or other expandable memberwhich applies the force upon expansion. In some embodiments, the tissuepenetrating member is configured to be directly coupled to a structureapplying the force (e.g. a spring, a shaft and the like or even anexpandable device). In these and related embodiments, the tissuepenetrating member is configured to detach from a structure applying theforce when a direction of the force changes.

Various aspects of the invention also provide other embodiments of aswallowable delivery device for the delivery of medications 100 inaddition to those described above. According to one or more suchembodiments, the swallow delivery device can include one or moreexpandable balloons or other expandable devices for use in deliveringone or more tissue penetrating members including medication 100 into thewall of an intestine, such as the small intestine. Referring now toFIGS. 12-20, another embodiment of a device 110 for the delivery ofmedication 100 to a delivery site DS in the gastro-intestinal (GI)tract, can comprise a capsule 120 sized to be swallowed and pass throughthe intestinal tract, a deployment member 130, one or more tissuepenetrating members 140 containing medication 100, a deployable aligner160 and a delivery mechanism 170. In some embodiments, medication 100(also referred to herein as preparation 100) may itself comprise tissuepenetrating member 140. The deployable aligner 160 is positioned withinthe capsule and configured to align the capsule with the intestine suchas the small intestine. Typically, this will entail aligning alongitudinal axis of the capsule with a longitudinal axis of theintestine; however, other alignments are also contemplated. The deliverymechanism 170 is configured for delivering medication 100 into theintestinal wall and will typically include a delivery member 172 such asan expandable member. The deployment member 130 is configured fordeploying at least one of the aligner 160 or the delivery mechanism 170.As will be described further herein, all or a portion of the capsulewall is degradable by contact with liquids in the GI tract so as toallow those liquids to trigger the delivery of medication 100 by device110. As used herein, “GI tract” refers to the esophagus, stomach, smallintestine, large intestine and anus, while “Intestinal tract” refers tothe small and large intestine. Various embodiments of the invention canbe configured and arranged for delivery of medication 100 into both theintestinal tract as well as the entire GI tract.

Device 110 including tissue penetrating member 140 can be configured forthe delivery of liquid, semi-liquid or solid forms of medication 100 orcombinations of all three. Whatever the form, medication 100 desirablyhas a material consistency allowing the medication to be advanced out ofdevice 110, into the intestinal wall (small or large intestine) or otherluminal wall in the GI tract and then degrade within the intestinal wallto release the drug or other therapeutic agent 101 into the wall andthen into the blood stream. The material consistency of medication 100can include one or more of the hardness, porosity and solubility of thepreparation (in body fluids such as those found in the wall of the smallintestine). The material consistency can be achieved by selection anduse of one or more of the following: i) the compaction force used tomake the preparation; ii) the use of one or more pharmaceuticaldisintegrants known in the art; iii) use of other pharmaceuticalexcipients; iv) the particle size and distribution of the preparation(e.g., micronized particles); and v) use of micronizing and otherparticle formation methods known in the art.

Capsule 120 is sized to be swallowed and pass through the intestinaltract. The size can also be adjusted depending upon the amount of drugto be delivered as well as the patient's weight and adult vs. pediatricapplications. Typically, the capsule will have a tubular shape withcurved ends similar to a vitamin. In these and related embodiments,capsule lengths 120L can be in the range of 0.5 to 2 inches anddiameters 120D in the range of 0.1 to 0.5 inches with other dimensionscontemplated. The capsule 120 includes a capsule wall 121 w, having anexterior surface 125 and an interior surface 124 defining an interiorspace or volume 124 v. In some embodiments, the capsule wall 121 w caninclude one or more apertures 126 sized for the outward advancement oftissue penetrating members 140. In addition to the other components ofdevice 110, (e.g., the expandable member etc.) the interior volume caninclude one or more compartments or reservoirs 127.

The capsule can be fabricated from various biodegradable gelatinmaterials known in the pharmaceutical arts, but can also include variousenteric coatings 120 c, configured to protect the cap from degradationin the stomach (due to acids etc.), and then subsequently degrade in thein higher pH's found in the small intestine or other area of theintestinal tract. In various embodiments, the capsule 120 can be formedfrom multiple portions one or more of which may be biodegradable. Inmany embodiments, capsule 120 can be formed from two portions 120 p suchas a body portion 120 p″ (herein body 120 p″) and a cap portion 120 p′(herein cap 120 p), where the cap fits onto the body, e.g., by slidingover or under the body (with other arrangements also contemplated). Oneportion, such as the cap 120 p′, can include a first coating 120 c′configured to degrade above a first pH (e.g., pH 5.5) and the secondportion such as the body 120 p″ can include a second coating 120 c″configured to degrade above a second higher pH (e.g. 6.5). Both theinterior 124 and exterior 125 surfaces of capsule 120 are coated withcoatings 120 c′ and 120 c″ so that that either portion of the capsulewill be substantially preserved until it contacts fluid having theselected pH. For the case of body 120 p″ this allows the structuralintegrity of the body 120 p″ to be maintained so as to keep balloon 172inside the body portion and not deployed until balloon 130 has expanded.Coatings 120 c′ and 120 c″ can include various methacrylate and ethylacrylate based coatings such as those manufactured by Evonik Industriesunder the trade name EUDRAGIT. These and other dual coatingconfigurations of the capsule 120 allows for mechanisms in one portionof capsule 120 to be actuated before those in the other portion of thecapsule. This is due to the fact that intestinal fluids will first enterthose portions where the lower pH coating has degraded thus actuatingtriggers which are responsive to such fluids (e.g., degradable valves).In use, such dual coating embodiments for capsule 120 provide fortargeted drug delivery to a particular location in the small intestine(or other location in the GI tract), as well as improved reliability inthe delivery process. This is due to the fact that deployment of aparticular component, such as aligner 160, can be configured to begin inthe upper area of the small intestine (e.g., the duodenum) allowing thecapsule to be aligned within the intestine for optimal delivery of thedrug (e.g., into the intestinal wall) as well as providing sufficienttime for deployment/actuation of other components to achieve drugdelivery into the intestinal wall while the capsule is still in thesmall intestine or other selected location.

As is discussed above, one or more portions of capsule 120 can befabricated from various biocompatible polymers known in the art,including various biodegradable polymers which in a preferred embodimentcan comprise cellulose, gelatin materials and PGLA(polylactic-co-glycolic acid). Other suitable biodegradable materialsinclude various enteric materials described herein as well as lactide,glycolide, lactic acid, glycolic acid, para-dioxanone, caprolactone,trimethylene carbonate, caprolactone, blends and copolymers thereof.

In various embodiments, the wall 120 w of the capsule is configured tobe degradable by contact with liquids in the GI tract, for exampleliquids, in the small intestine. In preferred embodiments, the capsulewall is configured to remain intact during passage through the stomach,but then to be degraded in the small intestine. In one or moreembodiments, this can be achieved by the use of an outer coating orlayer 120 c on the capsule wall 120 w, which only degrades in the higherpH's found in the small intestine and serves to protect the underlyingcapsule wall from degradation within the stomach before the capsulereaches the small intestine (at which point the drug delivery process isinitiated by degradation of the coating as is described herein). In use,such coatings allow for the targeted delivery of a therapeutic agent ina selected portion of the intestinal tract such as the small intestineincluding for example, into the wall of the small intestine.

Similar to capsule 20, in various embodiments, capsule 120 can includevarious radio-opaque, echogenic or other materials for location of thedevice using one or more medical imaging modalities known in the artsuch as fluoroscopy, ultrasound, MRI, etc. Such materials can bearranged in distinct bands or other shapes on the capsule so to readilyprovide visual indicators of the capsule in the intestinal tract usingthe one or more medical imaging modalities. They may also be configuredto allow the physician to discern if the capsule has or has notdeployed.

As is discussed further herein, in many embodiments, one or more of thedeployment member 130, delivery member 172 or deployable aligner 160,may correspond to an expandable balloon that is shaped and sized to fitwithin capsule 120. Accordingly, for ease of discussion, deploymentmember 130, delivery member 172 and deployable aligner 160 will now bereferred to as balloon 130, 160 and 172; however, it should beappreciated that other devices including various expandable devices arealso contemplated for these elements and may include for example,various shape memory devices (e.g., an expandable basket made from shapememory biodegradable polymer spires), expandable piezo electric devices,and/or chemically expandable devices having an expanded shape and sizecorresponding to the interior volume 124 v of the capsule 120.

One or more of balloons 130, 160 and 172 can comprise various polymersknown in the medical device arts. In preferred embodiments such polymerscan comprise one or more types of polyethylene (PE) which may correspondto low density PE (LDPE), linear low density PE (LLDPE), medium densityPE (MDPE) and high density PE (HDPE) and other forms of polyethyleneknown in the art. In one more embodiments using polyethylene, thematerial may be cross-linked using polymer irradiation methods known inthe art so. In particular embodiments radiation-based cross-linking maybe used as to control the inflated diameter and shape of the balloon bydecreasing the compliance of the balloon material. The amount orradiation may be selected to achieve a particular amount of crosslinking to in turn produce a particular amount of compliance for a givenballoon, e.g., increased irradiation can be used to produce stiffer lesscompliant balloon material. Other suitable polymers can include PET(polyethylene teraphalate), silicone and polyurethane. In variousembodiments balloons 130, 160 and 172 may also include variousradio-opaque materials known in the art such as barium sulfate to allowthe physician to ascertain the position and physical state of theballoon (e.g., un-inflated, inflated or punctures. Balloons 130, 160 and172 can be fabricated using various balloon blowing methods known in theballoon catheters arts (e.g., mold blowing, free blowing, etc.) to havea shape and size which corresponds approximately to the interior volume124 v of capsule 120. In various embodiments one or more of balloons130, 160 and 172 and various connecting features (e.g., connectingtubes) can have a unitary construction being formed from a single mold.Embodiments employing such unitary construction provide the benefit ofimproved manufacturability and reliability since fewer joints must bemade between one or more components of device 110.

Suitable shapes for balloons 130, 160 and 172 include variouscylindrical shapes having tapered or curved end portions (an example ofsuch a shape including a hot dog). In some embodiments, the inflatedsize (e.g., diameter) of one or more of balloons 130, 160 and 172, canbe larger than capsule 120 so as to cause the capsule to come apart fromthe force of inflation, (e.g., due to hoop stress). In other relatedembodiments, the inflated size of one or more of balloons 130, 160 and172 can be such that when inflated: i) the capsule 120 has sufficientcontact with the walls of the small intestine so as to elicit aperistaltic contraction causing contraction of the small intestinearound the capsule, and/or ii) the folds of the small intestine areeffaced to allow. Both of these results allow for improved contactbetween the capsule/balloon surface and the intestinal wall so asdeliver tissue penetrating members 40 over a selected area of thecapsule and/or delivery balloon 172. Desirably, the walls of balloons130, 160 and 172 will be thin and can have a wall thickness in the rangeof 0.005 to 0.0001″ more preferably, in the range of 0.005 to 0.0001,with specific embodiments of 0.004, 0.003, 0.002, 0.001, and 0.0005).Additionally in various embodiments, one or more of balloon 130, 160 or172 can have a nested balloon configuration having an inflation chamber160IC and extended finger 160EF as is shown in the embodiments of FIG.13c . The connecting tubing 163, connecting the inflation chamber 160ICcan be narrow to only allow the passage of gas 168, while the connectingtubing 36 coupling the two halves of balloon 130 can be larger to allowthe passage of water.

As indicated above, the aligner 160 will typically comprise anexpandable balloon and for ease of discussion, will now be referred toas aligner balloon 160 or balloon 160. Balloon 160 can be fabricatedusing materials and methods described above. It has an unexpanded andexpanded state (also referred to as a deployed state). In its expandedor deployed state, balloon 160 extends the length of capsule 120 suchthat forces exerted by the peristaltic contractions of the smallintestine SI on capsule 120 serve to align the longitudinal axis 120LAof the capsule 120 in a parallel fashion with the longitudinal axis LAIof the small intestine SI. This in turn serves to align the shafts oftissue penetrating members 140 in a perpendicular fashion with thesurface of the intestinal wall IW to enhance and optimize thepenetration of tissue penetrating members 140 into the intestinal wallIW. In addition to serving to align capsule 120 in the small intestine,aligner 160 is also configured to push delivery mechanism 170 out ofcapsule 120 prior to inflation of delivery balloon 172 so that thedelivery balloon and/or mechanism is not encumbered by the capsule. Inuse, this push out function of aligner 160 improves the reliability fordelivery of the therapeutic agent since it is not necessary to wait forparticular portions of the capsule (e.g., those overlying the deliverymechanism) to be degraded before drug delivery can occur.

Balloon 160 may be fluidically coupled to one or more components ofdevice 110 including balloons 130 and 172 by means of polymer tube orother fluidic couplings 162 which may include a tube 163 for couplingballoons 160 and 130 and a tube 164 for coupling balloon 160 and balloon172. Tube 163 is configured to allow balloon 160 to be expanded/inflatedby pressure from balloon 130 (e.g., pressure generated the mixture ofchemical reactants within balloon 130) and/or otherwise allow thepassage of liquid between balloons 130 and 160 to initiate a gasgenerating chemical reaction for inflation of one or both of balloons130 and 160. Tube 164 connects balloon 160 to 172 so as to allow for theinflation of balloon 172 by balloon 160. In many embodiments, tube 164includes or is coupled to a control valve 155 which is configured toopen at a selected pressure so as to control the inflation of balloon172 by balloon 160. Tube 164 may thus comprise a proximal portion 164 pconnecting to the valve and a distal portion 164 d leading from thevalve. Typically, proximal and distal portions 164 p and 164 d will beconnected to a valve housing 158 as is described below.

Valve 155 may comprise a triangular or other shaped section 156 of amaterial 157 which is placed within a the chamber 158 c of a valvehousing 158 (alternately, it may be placed directly within tubing 164).Section 157 is configured to mechanically degrade (e.g., tears, shears,delaminates, etc.) at a selected pressure so as to allow the passage ofgas through tube 164 and/or valve chamber 158 c. Suitable materials 157for valve 155 can include bees wax or other form of wax and variousadhesives known in the medical arts which have a selectable sealingforce/burst pressure. Valve fitting 158 will typically comprise a thincylindrical compartment (made from biodegradable materials) in whichsection 156 of material 157 is placed (as is shown in the embodiment ofFIG. 13b ) so as to seal the walls of chamber 158 c together orotherwise obstruct passage of fluid through the chamber. The releasepressure of valve 155 can be controlled through selection of one or moreof the size and shape of section 156 as well as the selection ofmaterial 157 (e.g., for properties such as adhesive strength, shearstrength etc.). In use, control valve 155 allows for a sequencedinflation of balloon 160 and 172 such that balloon 160 is fully orotherwise substantially inflated before balloon 172 is inflated. This,in turn, allows balloon 160 to push balloon 172 along with the rest ofdelivery mechanism 170 out of capsule 120 (typically from body portion120 p′) before balloon 172 inflates so that deployment of tissuepenetrating members 140 is not obstructed by capsule 120. In use, suchan approach improves the reliability of the penetration of tissuepenetrating members 140 into intestinal wall IW both in terms ofachieving a desired penetration depth and delivering greater numbers ofthe penetrating members 140 contained in capsule 120 since theadvancement of the members into intestinal wall IW is not obstructed bycapsule wall 120 w.

As is describe above, the inflated length 1601 of the aligner balloon160 is sufficient to have the capsule 120 become aligned with thelateral axis of the small intestine from peristaltic contractions of theintestine. Suitable inflated lengths 1601 for aligner 160 can include arange between about ½ to two times the length 120 l of the capsule 120before inflation of aligner 160. Suitable shapes for aligner balloon 160can include various elongated shapes such as a hotdog like shape. Inspecific embodiments, balloon 160 can include a first section 160′ and asecond section 160″, where expansion of first section 160′ is configuredto advance delivery mechanism 170 out of capsule 120 (typically out ofand second section 160″ is used to inflate delivery balloon 172. Inthese and related embodiments, first and second sections 160′ and 160″can be configured to have a telescope-style inflation where firstsection 160′ inflates first to push mechanism 170 out of the capsule(typically from body portion 120 p′) and second section 160″ inflates toinflate delivery member 172. This can be achieve by configuring firstsection 160′ to have smaller diameter and volume than second section160″ such that first section 160′ inflates first (because of its smallervolume) and with second section 160″ not inflating until first section60′ has substantially inflated. In one embodiment, this can befacilitated by use of a control valve 155 (described above) connectingsections 160′ and 160″ which does not allow passage of gas into section160″ until a minimum pressure has been reached in section 160′. In someembodiments, the aligner balloon can contain the chemical reactantswhich react upon mixture with water or other liquid from the deployingballoon.

In many embodiments, the deployment member 130 will comprise anexpandable balloon, known as the deployment balloon 130. In variousembodiments, deployment balloon 30 is configured to facilitatedeployment/expansion of aligner balloon 160 by use of a gas, forexample, generation of a gas 169 from a chemical. The gas may begenerated by the reaction of solid chemical reactants 165, such as anacid 166 (e.g., citric acid) and a base 166 (e.g., potassiumbicarbonate, sodium bicarbonate and the like) which are then mixed withwater or other aqueous liquid 168. The amount of reactants can be chosenusing stoichiometric methods to produce a selected pressure in one ormore of balloons 130, 160 and 72. The reactants 165 and liquids can bestored separately in balloon 130 and 160 and then brought together inresponse to a trigger event, such as the pH conditions in the smallintestine. The reactants 165 and liquids 168 can be stored in eitherballoon, however in preferred embodiments, liquid 168 is stored inballoon 130 and reactants 165 in balloon 160. To allow for passage ofthe liquid 168 to start the reaction and/or the resulting gas 169,balloon 130 may be coupled to aligner balloon 160 by means of aconnector tube 163 which also typically includes a separation means 150such as a degradable valve 150 described below. For embodiments whereballoon 130 contains the liquid, tube 163 has sufficient diameter toallow for the passage of sufficient water from balloon 130 to balloon 60to produce the desired amount of gas to inflate balloon 160 as wellinflate balloon 172. Also when balloon 130 contains the liquid, one orboth of balloon 30 and tube 63 are configured to allow for the passageof liquid to balloon 160 by one or more of the following: i) thecompressive forced applied to balloon 130 by peristaltic contractions ofthe small intestine on the exposed balloon 130; and ii) wicking ofliquid through tube 163 by capillary action.

Tube 163 will typically include a degradable separation valve or otherseparation means 150 which separates the contents of balloon 130, (e.g.,water 158) from those of balloon 160 (e.g., reactants 165) until thevalve degrades. Valve 150 can be fabricated from a material such asmaltose, which is degradable by liquid water so that the valve opensupon exposure to water along with the various liquids in the digestivetract. It may also be made from materials that are degradable responsiveto the higher pH's found in the intestinal fluids such as methacrylatebased coatings. The valve is desirably positioned at location on tube163 which protrudes above balloon 130 and/or is otherwise sufficientexposed such that when cap 120 p′ degrades the valve 150 is exposed tothe intestinal liquids which enter the capsule. In various embodiments,valve 150 can be positioned to lie on the surface of balloon 130 or evenprotrude above it (as is shown in the embodiments of FIGS. 16a and 16b), so that is has clear exposure to intestinal fluids once cap 120 p′degrades. Various embodiments of the invention provide a number ofstructures for a separation valve 150, for example, a beam likestructure (where the valve comprises a beam that presses down on tube163 and/or connecting section 136), or collar type structure (where thevalve comprise a collar lying over tube 163 and/or connecting section136). Still other valve structures are also contemplated.

Balloon 130 (or other expandable deployment device 130) has a deployedand a non-deployed state. In the deployed state, the deployment balloon130 can have a dome shape 130 d which corresponds to the shape of an endof the capsule. Other shapes 130 s for the deployed balloon 130 are alsocontemplated, such as spherical, tube-shape, etc. The reactants 165 willtypically include at least two reactants 166 and 167, for example, anacid such as citric acid and a base such as sodium bicarbonate. Otherreactants 165 including other acids, e.g., acetic acid and bases, e.g.,sodium hydroxide are also contemplated. When the valve or otherseparation means 150 opens, the reactants mix in the liquid and producea gas such as carbon dioxide which expands the aligner balloon 160 orother expandable member.

In an alternative embodiment shown in FIG. 13b , the deployment balloon130 can actually comprise a first and second balloon 130′ and 130″connected by a tube 36 or other connection means 136 (e.g., a connectingsection). Connecting tube 136 will typically include a separation valve150 that is degradable by a liquid as described above and/or a liquidhaving a particular pH such as basic pH found in the small intestine(e.g., 5.5 or 6.5). The two balloons 130′ and 130″ can each have a halfdome shape 130 hs allowing them to fit into the end portion of thecapsule when in the expanded state. One balloon can contain the chemicalreactant(s) 165 (e.g., sodium bicarbonate, citric acid, etc.) the otherthe liquid water 168, so that when the valve is degraded the twocomponents mix to form a gas which inflates one or both balloons 130′and 130″ and in turn, the aligner balloon 160.

In yet another alternative embodiment, balloon 130 can comprise amulti-compartment balloon 130 mc, that is formed or other constructed tohave multiple compartments 130 c. Typically, compartments 130 c willinclude at least a first and a second compartment 134 and 135 which areseparated by a separation valve 150 or other separation means 150 as isshown in the embodiment of FIG. 14a . In many embodiments, compartments134 and 135 will have at least a small connecting section 136 betweenthem which is where separation valve 150 will typically be placed. Aliquid 168, typically water, can be disposed within first compartment134 and one or more reactants 165 disposed in second compartment 135(which typically are solid though liquid may also be used) as is shownin the embodiment of FIG. 14a . When valve 150 opens (e.g., fromdegradation caused by fluids within the small intestine) liquid 168enters compartment 135 (or vice versa or both), the reactant(s) 165 mixwith the liquid and produce a gas 169 such as carbon dioxide whichexpands balloon 130 which in turn can be used to expand one or more ofballoons 160 and 172.

Reactants 165 will typically include at least a first and a secondreactant, 166 and 167 for example, an acid such as citric acid and abase such as sodium bi-carbonate or potassium bi-carbonate. As discussedherein, in various embodiments they may be placed in one or more ofballoon 130 (including compartments 134 and 135 or halves 130′ and 130″)and balloon 160. Additional reactants, including other combinations ofacids and bases which produce an inert gas by product are alsocontemplated. For embodiments using citric acid and sodium or potassiumbicarbonate, the ratios between the two reactants (e.g., citric acid topotassium bicarbonate) can be in the range of about 1:1 to about 1:4,with a specific ratio of about 1:3. Desirably, solid reactants 165 havelittle or no absorbed water. Accordingly, one or more of the reactants,such as sodium bicarbonate or potassium bicarbonate can be pre-dried(e.g., by vacuum drying) before being placed within balloon 130. Otherreactants 165 including other acids, e.g., acetic acid and bases arealso contemplated. The amounts of particular reactants 165, includingcombinations of reactants can be selected to produce particularpressures using known stoichiometric equations for the particularchemical reactions as well as the inflated volume of the balloon and theideal gas law (e.g., PV=nRT). In particular embodiments, the amounts ofreactants can be selected to produce a pressure selected one or more ofballoons 130, 160 and 172 to: i) achieve a particular penetration depthinto the intestinal wall; and produce a particular diameter for one ormore of balloons 130, 160 and 172; and iii) exert a selected amount offorce against intestinal wall IW. In particular embodiments, the amountand ratios of the reactants (e.g., citric acid and potassiumbicarbonate) can be selected to achieve pressures in one more of theballoons 130, 160 and 172 in the range of 10 to 15 psi, with smaller andlarger pressures contemplated. Again the amounts and ratios of thereactants to achieve these pressures can be determined using knownstoichiometric equations.

In various embodiments of the invention using chemical reactants 165 togenerate gas 169, the chemical reactants alone or in combination withthe deployment balloon 130 can comprise a deployment engine for 180deploying one or both of the aligner balloon 160 and delivery mechanism170 including delivery balloon 172. Deployment engine 180 may alsoinclude embodiments using two deployment balloons 130 and 130″ (a dualdome configuration as shown in FIG. 13b ), or a multi compartmentballoon 130 mc as shown in FIG. 14a . Other forms of a deployment engine180 are also contemplated by various embodiments of the invention suchas use of expandable piezo-electric materials (that expand byapplication of a voltage), springs and other shape memory materials andvarious thermally expandable materials.

One or more of the expandable balloons 130, 160 and 172 will alsotypically include a deflation valve 159 which serves to deflate theballoon after inflation. Deflation valve 159 can comprise biodegradablematerials which are configured to degrade upon exposure to the fluids inthe small intestine and/or liquid in one of the compartments of theballoon so as to create an opening or channel for escape of gas within aparticular balloon. Desirably, deflation valves 159 are configured todegrade at a slower rate than valve 150 to allow sufficient time forinflation of balloons, 130, 160 and 172 before the deflation valvedegrades. In various embodiments, of a compartmentalized balloon 130,deflation valve 159 can correspond to a degradable section 139positioned on an end portion 131 of the balloon as is shown in theembodiment of FIG. 14a . In this and related embodiments, whendegradable section 139 degrades from exposure to the liquid, balloonwall 132 tears or otherwise comes apart providing for a high assuranceof rapid deflation. Multiple degradable sections 139 can be placed atvarious locations within balloon wall 132.

In various embodiments of balloon 172, deflation valve 159 cancorrespond to a tube valve 173 attached to the end 172 e of the deliveryballoon 172 (opposite to the end which is coupled to the alignerballoon) as is shown in the embodiment of FIG. 13b . The tube valve 173comprises a hollow tube 173 t having a lumen that is obstructed at aselected location 1731 with a material 173 m such as maltose thatdegrades upon exposure to fluid such as the fluid in the smallintestine. The location 1731 of the obstructing material 173 m in tube173 t is selected to provide sufficient time for the delivery balloon172 to inflate and deliver the tissue penetrating members 40 into theintestinal wall IW before the obstructing material dissolves to openvalve 173. Typically, this will be close to the end 173 e of the tube173 t, but not quite so as to allow time for liquid to have to wick intothe tube lumen before it reaches material 173 m. According to one ormore embodiments, once the deflation valve 173 opens, it not only servesto deflate the delivery balloon 172 but also the aligner balloon 160 anddeployment balloon 130 since in many embodiments, all three arefluidicially connected (aligner balloon being fluidically connected todelivery balloon 172 and the deployment balloon 130 being fluidicallyconnected to aligner balloon 160). Opening of the deflation valve 173can be facilitated by placing it on the end 172 e of the deliveryballoon 172 that is forced out of capsule 120 by inflation of thealigner balloon 160 so that the deflation valve has good exposure toliquids in the small intestine. Similar tube deflation valves 173 canalso be positioned on one or both of aligner balloon 162 and thedeployment balloon 130. In these later two cases, the obstructingmaterial in the tube valve can be configured to degrade over a timeperiod to allow sufficient time for inflation of delivery balloon 172and advancement of tissue penetrating members 140 into the intestinalwall.

Additionally, as further backup for insured deflation, one or morepuncture elements 182 can be attached to the inside surface 124 of thecapsule such that when a balloon (e.g., balloon 130, 160, 172) fullyinflates it contacts and is punctured by the puncture element 182.Puncture elements 182 can comprise short protrusions from surface 124having a pointed tip. In another alternative or additional embodiment ofmeans for balloon deflation, one or more of the tissue penetratingmembers 140 can be directly coupled to the wall of 172 w of balloon 172and configured to tear away from the balloon when they detach, tearingthe balloon wall in the process.

A discussion will now be presented of tissue penetrating members 140.Tissue penetrating member 140 can be fabricated from various drugs andother therapeutic agents 101, one or more pharmaceutical excipients(e.g., disintegrants, stabilizers, etc.) and one or more biodegradablepolymers. The later materials chosen to confer desired structural andmaterial properties to the penetrating member (for example, columnstrength for insertion into the intestinal wall, or porosity andhydrophilicity for control the release of drug). Referring now to FIGS.18a-18f , in many embodiments, the penetrating member 140 can be formedto have a shaft 144 and a needle tip 145 or other pointed tip 145 so asto readily penetrate tissue of the intestinal wall as shown in theembodiment of FIG. 18a . In preferred embodiments, tip 145 has a trocarshape as is shown in the embodiment of FIG. 18c . Tip 145 may comprisevarious degradable materials (within the body of the tip or as acoating), such as sucrose or other sugar which increase the hardness andtissue penetrating properties of the tip. Once placed in the intestinalwall, the penetrating member 140 is degraded by the interstitial fluidswithin the wall tissue so that the drug or other therapeutic agent 101dissolves in those fluids and is absorbed into the blood stream. One ormore of the size, shape and chemical composition of tissue penetratingmember 140 can be selected to allow for dissolution and absorption ofdrug 101 in a matter of seconds, minutes or even hours. Rates ofdissolution can be controlled through the use of various disintegrantsknown in the pharmaceutical arts. Examples of disintegrants include, butare not limited to, various starches such as sodium starch glycolate andvarious cross linked polymers such as carboxymethyl cellulose. Thechoice of disintegrants can be specifically adjusted for the environmentwithin the wall of the small intestine and/or peritoneal wall.

Tissue penetrating member 140 will also typically include one or moretissue retaining features 143 such as a barb or hook to retain thepenetrating member within the tissue of the intestinal wall IW afteradvancement. Retaining features 143 can be arranged in various patterns143 p to enhance tissue retention such as two or more barbssymmetrically or otherwise distributed around and along member shaft 144as is shown in the embodiments of FIGS. 18a and 18b . Additionally, inmany embodiments, penetrating member will also include a recess or othermating feature 146 for attachment to a coupling component on deliverymechanism 170.

Tissue penetrating member 140 is desirably configured to be detachablycoupled to platform 175 (or other component of delivery mechanism 170),so that after advancement of the tissue penetrating member 140 into theintestinal wall, the penetrating member detaches from the balloon.Detachability can be implemented by a variety of means including: i) thesnugness or fit between the opening 174 in platform 175 and the membershaft 144); ii) the configuration and placement of tissue retainingfeatures 143 on penetrating member 140; and iii) the depth ofpenetration of shaft 144 into the intestinal wall. Using one or more ofthese factors, penetrating member 140 be configured to detach as aresult of balloon deflation (where the retaining features 143 hold thepenetrating member 140 in tissue as the balloon deflates or otherwisepulls back away from the intestinal wall) and/or the forces exerted oncapsule 120 by a peristaltic contraction of the small intestine.

In a specific embodiment, the detachability and retention of tissuepenetrating member 140 in the intestinal wall IW can be enhanced byconfiguring the tissue penetrating member shaft 144 to have an inversetaper 144 t as is shown in the embodiment of FIG. 18c . The taper 144 ton the shaft 144 is configured such that the application of peristalticcontractile forces from the intestinal wall on the shaft result in theshaft being forced inward (e.g., squeezed inward). This is due to theconversion by shaft taper 144 t of the laterally applied peristalticforce PF to an orthogonal force OF acting to force the shaft inward intothe intestinal wall. In use, such inverse tapered shaft configurationsserve to retain tissue penetrating member 140 within the intestinal wallso as to detach from platform 175 (or other component of deliverymechanism 170) upon deflation of balloon 172. In additional embodiments,tissue penetrating members 140 having an inverse tapered shaft may alsoinclude one or more retaining features 143 to further enhance theretention of the tissue penetrating member within intestinal wall IWonce inserted.

As described above, in various embodiments, tissue penetrating member140 can be fabricated from a number of drugs and other therapeuticagents 101. Also according to one or more embodiments, the tissuepenetrating member may be fabricated entirely from drug 101 (e.g. suchas an AP-antibody) or may have other constituent components as well,e.g., various pharmaceutical excipients (e.g., binders, preservatives,disintegrants, etc.), polymers conferring desired mechanical properties,etc. Further, in various embodiments one or more tissue penetratingmembers 140 can carry the same or a different drug 101 (or othertherapeutic agent) from other tissue penetrating members. The formerconfiguration allows for the delivery of greater amounts of a particulardrug 101 (e.g., a particular AP antibody), while the later, allows twoor more different drugs to be delivered into the intestinal wall atabout the same time to facilitate drug treatment regimens requiringsubstantial concurrent delivery of multiple drugs. In embodiments ofdevice 110, having multiple delivery assemblies 178 (e.g., two, one oneach face of balloon 172), a first assembly 178′ can carry tissuepenetrating members having a first drug 101 and a second assembly 178″can carry tissue penetrating members having a second drug 101.

Typically, the drug or other therapeutic agent 101 carried by the tissuepenetrating member 140 will be mixed in with a biodegradable material105 to form tissue penetrating member 140. Material 105 may include oneor more biodegradable polymers such as PGLA, cellulose, as well assugars such as maltose or other biodegradable material described hereinor known in the art. In such embodiments, the penetrating member 140 maycomprise a substantially heterogeneous mixture of drug 101 andbiodegradable material 105. Alternatively, the tissue penetrating member140 may include a portion 141 formed substantially from biodegradablematerial 105 and a separate section 142 that is formed from or containsdrug 101 as shown in the embodiment of FIG. 18d . In one or moreembodiments, section 142 may correspond to a pellet, slug, cylinder orother shaped section 142 s of drug 101. Shaped section 142 s may bepre-formed as a separate section which is then inserted into a cavity142 c in tissue penetrating member 140 as is shown in the embodiments ofFIGS. 18e and 18f . Alternatively section 142 s may be formed by addingof drug preparation 100 to cavity 142 c. In embodiments, where drugpreparation 100 is added to cavity 142 c, preparation may be added in asa powder, liquid, or gel which is poured or injected into cavity 142 c.Shaped section 142 s may be formed of drug 101 by itself or a drugpreparation containing drug 101 and one or more binders, preservatives,disintegrants and other excipients. Suitable binders includepolyethylene glycol (PEG) and other binders known in the art. In variousembodiments, the PEG or other binder may comprise in the range of about10 to 90% weight percent of the section 142 s, with a preferredembodiment for insulin preparations of about 25-90 weight percent. Otherexcipients which may be used for binders in tissue penetrating member140 may include for example, PLA, PLGA, Cyclodextrin, Cellulose, MethylCellulose, maltose, Dextrin, Sucrose and PGA. Further information on theweight percent of excipients in section 142 may be found in Table 3. Forease of discussion, section 142 is referred to as a pellet in the table,but the data in the table are also applicable to other embodiments ofsection 142 described herein.

In various embodiments, the weight of tissue penetrating member 140 canrange between about 10 to 15 mg, with larger and smaller weightscontemplated. For embodiments of tissue penetrating member 140fabricated from maltose, the weight can range from about 11 to 14 mg. Invarious embodiments, depending upon the drug 101 and the desireddelivered dose, the weight percent of drug in member 140 can range fromabout 0.1 to about 15%. In exemplary embodiments, these weight percentscorrespond to embodiments of members 140 fabricated from maltose orPGLA, however they are also applicable to any of the biodegradablematerials 105 used in the fabrication of members 140, for examplepolyethylene and other like materials. The weight percent of drug orother therapeutic agent 101 in member 140 can be adjusted depending uponthe desired dose as well as to provide for structural and stoichiometricstability of the drug and also to achieve a desired concentrationprofile of the drug in the blood or other tissue of the body. Variousstability tests and models (e.g., using the Arrhenius equation) known inthe art and/or known rates of drug chemical degradation may be used tomake specific adjustments in the weight percent range. Table 3 lists thedose and weight percent range for insulin and number of other drugswhich may be delivered by tissue penetrating member 140. In some cases,the table lists ranges as well a single value for the dose. It should beappreciated that these values are exemplary and other values recitedherein including those in claims are also considered. Further,embodiments of the invention also consider variations around thesevalues including for example, ±1, ±5, ±10, ±25, and even largervariations. Such variations are considered to fall within the scope ofan embodiment claiming a particular value or range of values. The tablealso lists the weight percentage of drug in section 142 for variousdrugs and other therapeutic agents, where again for ease of discussion,section 142 is referred to as a pellet. Again, embodiments of theinvention consider the variations described above.

TABLE 3 % Weight of % Weight of Drug in drug in Drug Dose Via Capsule**the needle pellet Insulin 4-9 units, 5-30 units, 1-50 units 2-15% 10-75%Exenatide 1-10 ug, 1-20 ug, 10 ug <1%, 0.1-1% 0.2-1%   Liraglutide 0.1-1mg, 0.5-2 mg, 0.6 mg 3-6%  25-40% Pramlintide 15-120 ug 0.1-1%  0.5-6%   Growth Hormone 0.2-1 mg, 0.1-4 mg 2-10% 10-50% Somatostatin and50-600 ug, 10-100 ug 0.3-8%    2-35% Analogs GnRH and Analogs 0.3-1.5mg, 0.1-2 mg 2-15% 15-75% Vasopressin 2-10 units <1%, 0.1-1% 0.2-1%  PTH and Analogues 0.1 to 10 ug, 10-30 ug, 20 ug 1-2%  0.5-2%  Interferons and analogs 1. For Multiple 0.03-0.25 mg 0.1-3%   1.5-15% Sclerosis 2. For Hep B and 6-20 ug 0.05-0.2%  0.2-1%   HepC Adalimumab1-5 mg, 2-4 mg 8-12% 70-90% Infliximab 1-10, 5 mg 8-12% 70-90%Etanercept 1-5 mg, 3 mg 8-12% 70-90% Natalizumab 1-5 mg, 3 mg 8-12%70-90%

Tissue penetrating member 140 can be fabricated using one or morepolymer and pharmaceutical fabrication techniques known in the art. Forexample, drug 101 (with or without biodegradable material 105) can be insolid form and then formed into the shape of the tissue penetratingmember 140 using molding, compaction or other like method with one ormore binding agents added. Alternatively, drug 101 and/or drugpreparation 100 may be in solid or liquid form and then added to thebiodegradable material 105 in liquid form with the mixture then formedinto the penetrating member 140 using molding or other forming methodknown in the polymer arts. In some embodiments, the tissue penetratingmember may have an outer layer or coating which has a slower rate ofdegradation in the intestinal wall (or surrounding tissue) then theinner body of the tissue penetrating so as to slow the rate of drugrelease into the blood stream. In various embodiments, the outer coatingor layer may have a rate of biodegradation that is 10, 25, 50, 100, 200,500, or a 1000% slower than that of the inner core. In use, suchembodiments allow for a delayed release of the drug 101.

Desirably, embodiments of the tissue penetrating member 140 comprising adrug or other therapeutic agent 101 and degradable material 105 areformed at temperatures which do not produce any substantial thermaldegradation of drug including drugs such as various peptides andproteins. This can be achieved through the use of room-temperaturecuring polymers and room temperature molding and solvent evaporationtechniques known in the art. In particular embodiments, the amount ofthermally degraded drug or other therapeutic agent within the tissuepenetrating member is desirably less than about 10% by weight and morepreferably, less than 5% and still more preferably less than 1%. Thethermal degradation temperature(s) for a particular drug are eitherknown or can be determined using methods known in the art and then thistemperature can be used to select and adjust the particular polymerprocessing methods (e.g., molding, curing, solvent evaporation methodsetc.) to minimize the temperatures and associated level of drug thermaldegradation.

A description will be provided of delivery mechanism 170. Typically, themechanism will comprise a delivery assembly 178 (containing tissuepenetrating members 140) that is attached to delivery balloon 172 as isshown in the embodiment of FIGS. 16a and 16b . Inflation of the deliveryballoon provides a mechanical force for engaging delivery assembly 172outwards from the capsule and into the intestinal wall IW so as toinsert tissue penetrating members 140 into the wall. In variousembodiments, the delivery balloon 172 can have an elongated shape withtwo relatively flat faces 172 f connected by an articulatedaccordion-like body 172 b. The flat faces 172 f can be configured topress against the intestinal wall (IW) upon expansion of the balloon 172so as to insert the tissue penetrating members (TPMs) 140 into theintestinal wall. TPMs 140 (either by themselves or as part of a deliveryassembly 178 described below) can be positioned on one or both faces 172f of balloon 172 to allow insertion of drug containing TPMs 40 onopposite sides of the intestinal wall. The faces 172 f of balloon 172may have sufficient surface area to allow for placement of a number ofdrug containing TPMs 140 on each face.

Referring now to FIG. 19, a description will now be provided of theassembly of delivery assembly 178. In a first step 300, one or moretissue penetrating members 140 can be detachably coupled to abiodegradable advancement structure 175 which may correspond to asupport platform 175 (also known as platform 175). In preferredembodiments, platform 175 includes one or more openings 174 forinsertion of members 140 as shown in step 300. Openings 174 are sized toallow for insertion and retention of members 140 in platform 175 priorto expansion of balloon 172 while allowing for their detachment from theplatform upon their penetration into the intestinal wall. Supportplatform 175 can then be positioned within a carrying structure 176 asshown in step 301. Carrying structure 176 may correspond to a wellstructure 176 having side walls 176 s and a bottom wall 176 b whichdefine a cavity or opening 176 c. Platform 175 is desirably attached toinside surface of bottom wall 176 b using adhesive or other joiningmethods known in the art. Well structure 176 can comprise variouspolymer materials and may be formed using vacuum forming techniquesknown in the polymer processing arts. In many embodiments, opening 176 ocan be covered with a protective film 177 as shown in step 302.Protective film 177 has properties selected to function as a barrier toprotect tissue penetrating members 140 from humidity and oxidation whilestill allowing tissue penetrating members 140 to penetrate the film asis described below. Film 177 can comprise various water and/or oxygenimpermeable polymers which are desirably configured to be biodegradablein the small intestine and/or to pass inertly through the digestivetract. It may also have a multi-ply construction with particular layersselected for impermeability to a given substance, e.g., oxygen, watervapor etc. In use, embodiments employing protective film 177 serve toincrease the shelf life of therapeutic agent 101 in tissue penetratingmembers 140, and in turn, the shelf life of device 110. Collectively,support platform 175 attached tissue penetrating members 140, wellstructure 176, and film 177 can comprise a delivery assembly 178.Delivery assemblies 178 having one or more drugs or therapeutic agents101 contained within tissue penetrating member 40 or other drug deliverymeans can be pre-manufactured, stored and subsequently used for themanufacture of device 110 at a later date. The shelf life of assembly178 can be further enhanced by filling cavity 176 c of the sealedassembly 178 with an inert gas such as nitrogen.

Referring back to FIGS. 16a and 16b , assemblies 178 can be positionedon one or both faces 172 f of balloon 172. In preferred embodiments,assemblies 178 are positioned on both faces 172 f (as shown in FIG. 16a) so as to provide a substantially equal distribution of force toopposite sides of the intestinal wall IW upon expansion of balloon 172.The assemblies 178 may be attached to faces 172 f using adhesives orother joining methods known in the polymer arts. Upon expansion ofballoon 172, TPMs 140 penetrate through film 177, enter the intestinalwall IW and are retained there by retaining elements 143 and/or otherretaining features of TPM 140 (e.g., an inverse tapered shaft 144 t)such that they detach from platform 175 upon deflation of balloon 172.

In various embodiments, one or more of balloons 130, 160 and 172 can bepacked inside capsule 120 in a folded, furled or other desiredconfiguration to conserve space within the interior volume 124 v of thecapsule. Folding can be done using preformed creases or other foldingfeature or method known in the medical balloon arts. In particularembodiments, balloon 130, 160 and 172 can be folded in selectedorientations to achieve one or more of the following: i) conserve space,ii) produce a desired orientation of a particular inflated balloon; andiii) facilitate a desired sequence of balloon inflations. Theembodiments shown in FIGS. 15a-15f illustrate an embodiment of a methodof folding and various folding arrangements. However, it should beappreciated that this folding arrangement and the resulting balloonorientations are exemplary and others may also be used. In this andrelated embodiments, folding can be done manually, by automated machineor a combination of both. Also in many embodiments, folding can befacilitated by using a single multi-balloon assembly 7 (herein assembly7) comprising balloons 130, 160, 170; valve chamber 158 and assortedconnecting tubings 162 as is shown in the embodiments of FIGS. 13a and13b . FIG. 13a shows an embodiment of assembly 7 having a single domeconstruction for balloon 130, while FIG. 13b shows the embodiment ofassembly 7 having dual balloon/dome configuration for balloon 130.Assembly 7 can be fabricated using a thin polymer film which isvacuum-formed into the desired shape using various vacuum forming andother related methods known in the polymer processing arts. Suitablepolymer films include polyethylene films having a thickness in the rangeof about 0.003 to about 0.010″, with a specific embodiment of 0.005″. Inpreferred embodiments, the assembly is fabricated to have a unitaryconstruction so as to eliminate the need for joining one or morecomponents of the assembly (e.g., balloons 130,160, etc.). However, itis also contemplated for assembly 7 to be fabricated from multipleportions (e.g., halves), or components (e.g., balloons) which are thenjoined using various joining methods known in the polymer/medical devicearts.

Referring now to FIGS. 15a-15f, 16a-16b and 17a-17b , in a first foldingstep 210, balloon 160 is folded over onto valve fitting 158 with balloon172 being flipped over to the opposite side of valve fitting 158 in theprocess (see FIG. 15a ). Then in step 211, balloon 172 is folded at aright angle to the folded combination of balloon 160 and valve 158 (seeFIG. 15b ). Then, in step 212 for dual dome embodiments of balloon 130,the two halves 130′ and 130″ of balloon 130 are folded onto each other,leaving valve 150 exposed (see FIG. 15c , for single dome embodiments ofballoon 130, is folded over onto itself see FIG. 15e ). A final foldingstep 213 can be done whereby folded balloon 130 is folded over 180° tothe opposite side of valve fitting 158 and balloon 160 to yield a finalfolded assembly 8 for dual dome configurations shown in the FIG. 15e anda final folded assembly 8′ for single dome configurations shown in FIGS.15e and 15f . One or more delivery assemblies 178 are then be attachedto assembly 8 in step 214 (typically two the faces 72 f of balloon 72)to yield a final assembly 9 (shown in the embodiments of FIGS. 16a and16b ) which is then inserted into capsule 120. After an insertion step215, the final assembled version of device 110 with inserted assembly 9is shown FIGS. 17a and 17 b.

Referring now to FIGS. 20a-20i , a description will be provided of amethod of using device 110 to deliver medication 101 to a site in the GItract such as the wall of the small or large intestine. It should beappreciated that the steps and there order is exemplary and other stepsand orders also contemplated. After device 110 enters the smallintestine SI, the cap coating 120 c′ is degraded by the basic pH in theupper small intestine causing degradation of cap 120 p′ as shown in step400 in FIG. 20b . Valve 150 is then exposed to fluids in the smallintestine causing the valve to begin degrade as is shown in step 401 inFIG. 20c . Then, in step 402, balloon 130 expands (due to generation ofgas 169) as shown in FIG. 20d . Then, in step 403, section 160′ ofballoon 160 begins to expand to start to push assembly 178 out of thecapsule body as shown in FIG. 20e . Then, in step 404, sections 160′ and160″ of balloon 160 become fully inflated to completely push assembly178 out of the capsule body extending the capsule length 120 l so as toserve to align capsule lateral axis 120AL with the lateral axis of thesmall intestine LAI as shown in FIG. 20f . During this time, valve 155is beginning to fail from the increased pressure in balloon 60 (due tothe fact that the balloon has fully inflated and there is no other placefor gas 169 to go). Then, in step 405, valve 155 has completely opened,inflating balloon 172 which then pushes the now completely exposedassembly 178 (having been pushed completely out of body 120 p″) radiallyoutward into the intestinal wall IW as shown in FIG. 20g . Then, in step406, balloon 172 continues to expand to now advance tissue penetratingmembers into the intestinal wall IW as shown in FIG. 20h . Then, in step407, balloon 172, (along with balloons 160 and 130) has deflated pullingback and leaving tissue penetrating members retained in the intestinalwall IW. Also, the body portion 120 p″ of the capsule has completelydegraded (due to degradation of coating 120 c″) along with otherbiodegradable portions of device 110. Any portion not degraded iscarried distally through the small intestine by peristaltic contractionfrom digestion and is ultimately excreted.

APPENDICES/EXAMPLES

Various embodiments of the invention are further illustrated withreference to the following appendices/examples. It should be appreciatedthat these examples are presented for purposes of illustration only andthat the invention is not to be limited to the information or thedetails therein.

Appendix 1 Modeling of Alirocumab Serum Concentration Vs Time

The following assumptions and/or data were used in modelling AlirocumabSerum Concentrations vs Time:

The subcutaneous dosing schedule is 150 mg every week, SC(subcutaneous), every two weeks, this corresponds to a daily dosingschedule of approximately 21.4 mg per day using embodiments of theinvention.

Monoclonal antibody was obtained from Regeneron/Sanofi. It targetspro-protein convertase subtilisin/kexin type 9 (PCSK9) to lower lowdensity lipoproteins (LDLs).

Pharmacokinetic parameters were obtained from: Lunven, C., Paehler, T.,Poitiers, F., et al. “A randomized study of the relativepharmacokinetics, pharmacodynamics, and safety of Alirocumab, a fullyhuman monoclonal antibody to PCSK9, after single subcutaneousadministration at three different injection sites in healthy subjects.”Cardiovascular Therapeutics, 2014, 32:297.301.

No ka was reported, but 0.5 day⁻¹ was chosen so that T_(max) was 4.3days.

The study reported PK parameters for three different sites of injectionand found that all three were comparable. For this single simulation,the parameters used were averages of the three.

When steady state is reached for simulated daily dosing usingembodiments of the invention, drug concentrations ranged from 10.06 mg/Lto 20.05 mg/L, resulting in an average of 15.06 mg/L.

When using embodiments of the invention, daily dosing at doses ofapproximately 10.5 mg every which corresponded approximately to the 150mg biweekly dose.

For daily dosing using embodiments of the invention, one can dose asmaller amount daily and receive the pharmacokinetic profile shown inFIG. 22 b.

Once steady state is reached, concentrations of Alirocumab ranged from15.41 mg/L to 15.47 mg/L, with an average steady state concentration of15.44 mg/L above the

15.06 value for subcutaneous injections every two weeks.

This lower day to day variation in drug concentrations may preventadverse events and anti-drug antibody formation, and the higher troughconcentrations ensure that biological activity of Alirocumab ismaintained.

Appendix 2 Model and Calculations Used for Calculation of Steady StateFluctuation in Alirocumab Serum Concentrations

% Steady State Fluctuation is a metric which provides an indication ofhow much variation there is in the patient's plasma/serum concentrationof drug over time. It is desirable to minimize steady state fluctuationfor multiple reasons. Firstly, drug concentrations that are higher thannecessary for pharmacologic activity are more likely to result inadverse events. In addition to specific effects for PCSK9 antibodies,such as myalgia, neurocognitive events and ophthalmologic events forPCSK9, antibody therapies cause anti-drug antibody production. Theseanti-drug antibodies target the drug and may neutralize them by blockingbinding sites or marking the drugs for destruction. A patient whodevelops anti-drug antibodies to a drug will no longer respond to thatdrug and must be placed on a different regimen. On the other hand, drugconcentrations that are lower than necessary for pharmacologic activityare also not desired. There is a greater chance of no pharmacologicactivity during these periods, and thus lower drug efficacy. It is idealto maintain a constant, steady level of pharmacologic activity in orderto effectively treat the targeted disorder.

TABLE 1 % Steady State Fluctuation for Alirocumab Alirocumab Current SCdosing 66.33% Rani dosing 0.39%

Calculations were made for % Steady State Fluctuation for the threeantibodies shown in Table 1. Values were determined using the existingpharmacokinetic simulations described in Appendix 1. The specificformula used to calculate % Steady State Fluctuation is shown below:

${\frac{C_{{ss},{peak}} - C_{{ss},{trough}}}{C_{{ss},{avg}}}*100} = {\% \mspace{14mu} {steady}\mspace{14mu} {state}\mspace{14mu} {fluctuation}}$

The above equation calculates the difference between peak steady stateconcentration (C_(ss,peak)) and trough steady state concentration(C_(ss,trough)) and divides by the average steady state concentration(C_(ss,avg)) to yield the percent change of serum drug concentrationsrelative to the average steady state drug concentration. Steady statefluctuation serves as a quantitative measure of how much we can expectserum drug concentrations to change in single dosing period.

From the data, it is evident that daily dosing using embodiments of theinvention allows much lower steady state fluctuation for the same drugsthan subcutaneous dosing. In addition to the expected benefits of lessfrequent, less intense adverse events and maintenance of pharmacologicactivity, dosing via injection into the small intestine usingembodiments of the invention avoids the injection site reactions thatmay occur in subcutaneous dosing.

CONCLUSION

The foregoing description of various embodiments of the invention hasbeen presented for purposes of illustration and description. It is notintended to limit the invention to the precise forms disclosed. Manymodifications, variations and refinements will be apparent topractitioners skilled in the art. For example, embodiments of the deviceand therapeutic preparations (e.g., in the form of a tissue penetratingmember) can be sized and otherwise adapted (e.g., dosage adjusted fortherapeutic preparations) for various pediatric and neonatalapplications as well as various veterinary applications. Also thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificdevices and methods described herein. Such equivalents are considered tobe within the scope of the present invention and are covered by theappended claims below.

Elements, characteristics, or acts from one embodiment can be readilyrecombined or substituted with one or more elements, characteristics oracts from other embodiments to form numerous additional embodimentswithin the scope of the invention. Moreover, elements that are shown ordescribed as being combined with other elements, can, in variousembodiments, exist as standalone elements. Hence, the scope of thepresent invention is not limited to the specifics of the describedembodiments, but is instead limited solely by the appended claims.

1. A therapeutic preparation comprising an anti-PCSK9 antibody(AP-antibody) in solid form, the preparation shaped as a solid tissuepenetrating member configured to penetrate and be inserted into anintestinal wall after oral ingestion by the application of force on thetissue penetrating member, wherein after insertion, the tissuepenetrating member is retained within the intestinal wall or surroundingtissue and releases the AP-antibody into the blood stream from theintestinal wall.
 2. The preparation of claim 1, wherein the tissuepenetrating member is structured as a shaft having a pointed end.
 3. Thepreparation of claim 2, wherein the tissue penetrating member has a dartlike or needle like structure.
 4. The preparation of claim 1, whereinthe force is a mechanical force.
 5. The preparation of claim 1, whereinthe AP-antibody is released into the blood stream from the intestinalwall to achieve a Cmax in a shorter time period than a time period toachieve a Cmax for an extravascularly injected dose of the AP-antibody.6. The preparation of claim 5, wherein a tmax for the AP-antibodyreleased from the tissue penetrating member is about 50% of a tmax forthe extravascularly injected dose of AP-antibody.
 7. The preparation ofclaim 5, wherein a tmax for the AP-antibody released from the tissuepenetrating member is about 30% of a tmax for the extravascularlyinjected dose of AP-antibody.
 8. The preparation of claim 5, wherein atmax for the AP-antibody released from the tissue penetrating member isabout 10% of a tmax for the extravascularly injected dose ofAP-antibody.
 9. The preparation of claim 5, wherein the extravascularinjection is a subcutaneous injection or an intramuscular injection. 10.The preparation of claim 1, wherein the preparation is adapted forinsertion into the wall of the small intestine.
 11. The preparation ofclaim 1, wherein the preparation is adapted to be orally delivered in aswallowable capsule.
 12. The preparation of claim 11, wherein thepreparation is adapted to be operably coupled to delivery means having afirst configuration and a second configuration, the preparation beingcontained within the capsule in the first configuration and advanced outof the capsule and into the intestinal wall in the second configuration.13. The preparation of claim 12, wherein the delivery means comprises aleast one expandable balloon having an expanded and a non-expanded stateand the first configuration is the non-expanded state and the secondconfiguration is the expanded state.
 14. The preparation of claim 1,wherein the preparation comprises a biodegradable material whichdegrades within the intestinal wall to release AP-antibody into theblood stream.
 15. The preparation of claim 1, wherein the biodegradablematerial comprises PGLA, polyethylene oxide, a sugar or maltose.
 16. Thepreparation of claim 1, wherein the preparation comprises at least onepharmaceutical excipient.
 17. The preparation of claim 16, wherein theat least one pharmaceutical excipient comprises at least one of abinder, a preservative or a disintegrant.
 18. The preparation of claim17, wherein the binder comprises PEG.
 19. The preparation of claim 1,wherein the tissue penetrating member comprises a biodegradable materialwhich degrades within the intestinal wall to release AP-antibody intothe blood stream.
 20. The preparation of claim 19, wherein thebiodegradable material comprises maltose or PGLA or polyethylene oxide.21. The preparation of claim 1 wherein a weight percent of AP-antibodyin the tissue penetrating member comprises between about 8 to 12%. 22.The preparation of claim 1, wherein the tissue penetrating memberincludes a retaining feature for retaining the tissue penetrating memberwithin the intestinal wall after insertion.
 23. The preparation of claim1, wherein the AP-antibody is contained in the tissue penetrating memberin a shaped section.
 24. The preparation of claim 23, wherein the shapedsection has a cylinder or pellet shape.
 25. The preparation of claim 1,wherein a Cmax achieved by delivering the preparation by insertion intothe intestinal wall is substantially greater than a Cmax achieved whenthe preparation is delivered orally without insertion into theintestinal wall.
 26. The preparation of claim 25, wherein the Cmaxachieved by delivering the preparation by insertion into the intestinalwall is at least about 100 times greater than the Cmax achieved when thepreparation is delivered orally without insertion into the intestinalwall.
 27. The preparation of claim 1, wherein the preparation isconfigured to produce a long-term release of AP-antibody.
 28. Thepreparation of claim 27, wherein the preparation is configured produce along-term release of AP-antibody to produce a selectable t½.
 29. Thepreparation of claim 28, wherein the t½ is about 40 days.
 30. Thepreparation of claim 1, wherein the AP-antibody is selected from thegroup consisting of Alirocumab, Evolocumab and Bococizumab.
 31. Thepreparation of claim 30, wherein when inserted into the intestinal wallof a patient on a daily basis, the preparation results in a percentsteady state fluctuation in plasma concentration of AP-antibody in thepatient in a range of about 0.12 to about 0.39%.
 32. The preparation ofclaim 1, wherein the AP-antibody is selected from the group consistingof adnectins, mimetic peptides, small molecule inhibitors, antisenseoligonucleotides, and RNA interence (RNA-i) compounds.
 33. Thepreparation of claim 1, wherein a dose of AP-antibody in the preparationis in a range from about 1 to 15 mg.
 34. The preparation of claim 33,wherein a dose of AP-antibody in the preparation is in a range fromabout 2 to 10 mg.
 35. A therapeutic preparation comprising an anti-PCSK9antibody (AP-antibody) in solid form, the preparation adapted forinsertion and retention in an intestinal wall after oral ingestion bythe application of force on the preparation, wherein upon insertion, thepreparation is degraded by fluids within the intestinal wall to releasethe AP-antibody into the bloodstream from the intestinal wall to achievea t½ that is greater than a t½ for orally ingested AP-antibody that isnot inserted into the intestinal wall.
 36. The preparation of claim 35,wherein the t½ of the AP-antibody inserted into the intestinal wall isat least about 10 times greater than the t½ for the orally ingestedAP-antibody that is not inserted into the intestinal wall.
 37. Thepreparation of claim 35, wherein the AP-antibody is selected from thegroup consisting of Alirocumab, Evolocumab and Bococizumab.
 38. Thepreparation of claim 35, wherein the force is a mechanical force.
 39. Atherapeutic preparation comprising Alirocumab in solid form, thepreparation shaped as a solid tissue penetrating member configured topenetrate and be inserted into an intestinal wall after oral ingestionby the application of mechanical force on the tissue penetrating member,wherein after insertion, the tissue penetrating member is retainedwithin the intestinal wall or surrounding tissue and releases theAlirocumab into the blood stream to reduce a LDL-C level in a patient.40. The preparation of claim 39, wherein when inserted into theintestinal wall of a patient on a daily basis, the preparation resultsin a percent steady state fluctuation in plasma concentration ofAlirocumab in the patient of about 0.39%.
 41. The preparation of claim39, wherein the preparation comprises about 10.5 mg of Alirocumab.
 42. Atherapeutic preparation comprising Evolocumab in solid form, thepreparation shaped as a solid tissue penetrating member configured topenetrate and be inserted into an intestinal wall after oral ingestionby the application of mechanical force on the tissue penetrating member,wherein after insertion, the tissue penetrating member is retainedwithin the intestinal wall or surrounding tissue and releases theEvolocumab into the blood stream to reduce a LDL-C level in a patient.43. The preparation of claim 42, wherein when inserted into theintestinal wall of a patient on a daily basis, the preparation resultsin a percent steady state fluctuation in plasma concentration ofEvolocumab in the patient in a range of about 0.12 to about 0.39%. 44.The preparation of claim 42, wherein the preparation comprises about 13to 15 mg of Evolocumab.
 45. A therapeutic preparation comprisingBococizumab in solid form, the preparation shaped as a solid tissuepenetrating member configured to penetrate and be inserted into anintestinal wall after oral ingestion by the application of mechanicalforce on the tissue penetrating member, wherein after insertion, thetissue penetrating member is retained within the intestinal wall orsurrounding tissue and releases the Bococizumab into the blood stream toreduce a LDL-C level in a patient.
 46. The preparation of claim 45,wherein when inserted into the intestinal wall of a patient on a dailybasis, the preparation results in a percent steady state fluctuation inplasma concentration of Bococizumab in the patient in a range of about0.12 to about 0.39%.
 47. The preparation of claim 45, wherein thepreparation comprises about 7 to 11 mg of Bococizumab.
 48. A method forreducing a LDL-C level in a patient having hypercholesterolemia, themethod comprising: providing a solid anti-PCSK9 antibody (AP-antibody)dosage shaped as a tissue penetrating member; penetrating the soliddosage AP-antibody into an intestinal wall after oral ingestion by theapplication of force on the tissue penetrating member such that thetissue penetrating member is retained in the intestinal wall orsurrounding tissue; and releasing the AP-antibody into the blood streamfrom the solid dosage AP-antibody in the intestinal wall or surroundingtissue to reduce the LDL-C level by binding of PCSK9 molecules by thereleased dosage of PCSK9 antibody. 49.-75. (canceled)
 76. A method fortreating hypercholesterolemia by in a patient by reducing the patient'sLDL-C level, the method comprising: providing a solid anti-PCSK9antibody (AP-antibody) dosage shaped as a tissue penetrating member;penetrating the solid dosage AP-antibody into an intestinal wall afteroral ingestion by the application of force on the tissue penetratingmember such that the tissue penetrating member is retained in theintestinal wall or surrounding tissue; releasing the AP-antibody intothe blood stream from the solid dosage AP-antibody in the intestinalwall or surrounding tissue to reduce the LDL-C level by binding of PCSK9molecules by the released dosage of PCSK9 antibody; monitoring an LDL-Clevel in the patient; and adjusting a dose of the AP antibody inresponse to the monitored LDL-C level in the patient. 77.-91. (canceled)92. A method for treating a cardiovascular condition in a patient byreducing the patients LDL-C level, the method comprising: providing asolid anti-PCSK9 antibody (AP-antibody) dosage shaped as a tissuepenetrating member; penetrating the solid dosage AP-antibody into anintestinal wall after oral ingestion by the application of force on thetissue penetrating member such that the tissue penetrating member isretained in the intestinal wall or surrounding tissue; releasing theAP-antibody into the blood stream from the solid dosage AP-antibody inthe intestinal wall or surrounding tissue to reduce the LDL-C level bybinding of PCSK9 molecules by the released dosage of PCSK9 antibody;monitoring an LDL-C level in the patient; and adjusting a dose of the APantibody in response to the monitored LDL-C level in the patient.93.-95. (canceled)
 96. A method for reducing a LDL-C level in a patienthaving hypercholesterolemia, the method comprising: providing a solidanti-PCSK9 antibody (AP-antibody) dosage shaped as a tissue penetratingmember; penetrating the solid dosage AP-antibody into an intestinal wallafter oral ingestion by the application of force on the tissuepenetrating member such that the tissue penetrating member is retainedin the intestinal wall or surrounding tissue; releasing the AP-antibodyinto the blood stream from the solid dosage AP-antibody in theintestinal wall or surrounding tissue to bind PCSK9 molecules; andorally administering an agent to reduce LDL-C levels, wherein LDL-Creducing agent acts in conjunction with AP-antibody to reduce LDL-Clevels. 97.-99. (canceled)